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The adaptation model of immunity Although ‘self–nonself’ and ‘danger’ theories have improved our understanding of the immune system, successful immunotherapy of cancer and many autoimmune diseases still remain far from reach. This indicates that our knowledge of how the immune system decides to respond effectively or ineffectively is limited. Emerging evidence suggest that decision-making during the immune response is not solely determined by ‘nonself’ entity of the antigen or damage-associated ‘danger’ signals. This article provides an overview of the ‘self–nonself’ and ‘danger’ models, and suggests that ‘adaptation’ signals are needed to guarantee immunological tolerance that has been observed during the immune response toward ‘self’, ‘nonself’ or even ‘danger’. This should be facilitated by dynamic expression of adapting receptors (ARs) and adapting ligands on cells of the immune system and other somatic cells. Any alterations in the expression of ARs on certain tissues would result in tissue-specific autoimmune diseases or spontaneous regression of cancer. Identification of such ARs and their nominal adapting ligands could lead to the discovery of currently unknown receptors and their implications in the treatment of cancer, solid organ transplantation and autoimmune diseases. KEYWORDS: APCs n autoimmune diseases n cancer immunotherapy n central tolerance n danger theory n graft-versus-host disease n immune tolerance n immunity n T cells

‘Self–nonself’ & ‘danger’ models of immunity The main function of the immune system is to recognize and protect the host from any threats that could be detrimental to the body. To accomplish this task, cells of the immune system have developed sensors that assist them in recognizing and responding to threats. There are two competing theories, that is, ‘self–nonself ’ and ‘danger’, for explaining how the immune system works. According to the ‘self–nonself ’ model of immunity, the adaptive immune system is designed to discriminate self from nonself and thus, it considers everything that is nonself or foreign as a threat. In other words, cells of the adaptive immune system express antigen-binding receptors as sensors of self or nonself proteins [1]. Cells of the innate immune system also express pathogen recognition receptors (PRR) that recognize the unique features of foreign pathogens termed pathogen-associated molecular patterns. For instance, Toll-like receptors (TLR) on APCs recognize conserved structures on microorganisms, thereby discriminating bacteria and viruses from autologous cells [2]. While this model is widely accepted and can explain allogeneic graft rejection, as well as graftversus-host disease (GVHD), it cannot explain the lack of an autoimmune reaction against foreign proteins in the food, tolerance of the

fetus during pregnancy, severe allergic reaction in some individuals (but not in everyone) to the foreign allergens, or autoimmune diseases induced by self-proteins. With the advancement in our understanding of the immune system, this theory has gone beyond the foreignness entity of the antigen and acknowledged the involvement of additional factors such as costimulation and peripheral tolerance to explain the tolerance towards foreign proteins. These additional factors keep adding to the picture by discovering more costimulatory molecules and diluting the impact that the entity of antigen might have on the immune function. The pathogen recognition receptors, including TLRs, were initially thought to be the sensors of foreign entities that facilitate the expression of costimulatory molecules such as B7‑1 and B7‑2 on APCs during the immune response. However, the self-ligand heat shock proteins (HSPs) and HMGB1 can also induce the expression of costimulatory molecules, indicating that the TLRs are not solely the sensors of foreign entities. In addition, the receptor for advanced glycation end-products is also a pathogen recognition receptor that is expressed on dendritic cells (DCs) [3] and T cells [4], which binds to self-proteins such as HMGB1 and induces the immune response. Despite these flaws, the ‘self–nonself ’ model remains valid providing explanation for the rejection

10.2217/IMT.13.157 © Masoud Manjili

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Masoud H Manjili Department of Microbiology & Immunology, Virginia Commonwealth University, Massey Cancer Center, Box 980035, 401 College Street, Richmond, VA 23298, USA Tel.: +1 804 828 8779 [email protected]

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of allogeneic grafts and tolerance of autologous grafts as well as the tolerance of cancerous cells that express self-proteins. To provide a better explanation for these phenomena, Matzinger proposed the ‘danger’ model of immunity [5]. In her model, the immune system is designed to recognize and react to ‘dangers’ which are causing damage, directly or indirectly, or mimic endogenous alarm signals such as HSPs or HMGB1. In other words, the immune system has evolved to recognize tissue damage rather than foreignness. According to this model, the mother’s immune system does not reject the fetus, nor does it destroy newly lactating breast tissue that has begun to produce milk proteins, because they are not dangerous to the host. The immune system does not react to foreign proteins in the food, because these antigenic targets are not dangerous to the human body and do not cause damage. Conversely, bacteria, viruses and parasites induce immune responses because they cause damage, not because they are foreign. According to the ‘danger’ model, the immune response is triggered by damage-associated molecular patterns from cells that are stressed, damaged and/or dying abnormally in the tissue. Damage-associated molecular patterns interact with their receptors on APCs and induce the expression of costimulatory molecules on DCs (signal II). This model suggests that unlike apoptosis, a necrotic cell death releases alarm signals for the initiation of the immune response. A number of alarm signals identified include: ƒƒ HSPs, which bind to TLR4 and scavenger receptors [6,7]; ƒƒ HMGB1, which binds to the receptor for advanced glycation end-products and TLR4 [3,8]; ƒƒ A splice variant of the fibronectin gene, the extradomain A, which binds to TLR4 [9]; ƒƒ Calreticulin, which binds to CD91 [6,10]; ƒƒ ATP, which binds to the purine nucleotide receptors (P2X7) [11]; ƒƒ RNA, which binds to TLR3 [12,13]; ƒƒ DNA, which binds to TLR9 [14] and uric acid [15]. Many of these alarm signals have been used as adjuvants in cancer vaccines to induce tumor antigen-specific immune responses [16,17]. Recently, the ‘danger’ theory has focused on the role of target tissues in regulating danger signal and inducing the immune response [18,19]. In 60

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her recent interview, Polly Matzinger proposed that the type of immune response is determined based on the tissue affected by danger signals [18]. In fact, the biological system tailors the class of immune response to the tissue in which it occurs, rather than the pathogen it is responding to. According to this model, each tissue dictates a specific type of immune response for protection from pathogens. For instance, the gut produces TGF-b, thereby dictating B cells to elicit an IgA response to retrovirus and suppressing Th1 responses, whereas the skin elicits a Th1 type of response to TB skin test, or strong IgG responses to viruses. Thus, rubella and measles viruses that inhabit the skin encounter IgG responses whereas retroviruses that inhabit the gut encounter IgA responses [19]. Tregs in the gut that produce IL-10 or TGF-b are not merely suppressor cells, rather they are required for regulating a normal immune response in the gut, which include strong IgA responses rather than Th1 responses. Therefore, any mutations in genes that regulate a proper tissue communication with the immune system can cause tissue-specific autoimmune diseases. A higher incidence of allergy and asthma in developed countries and in Olympic swimmers is because of the exposure to chlorine during daily showers and swimming; frequent exposure of the lung and skin to chlorine or other toxins affect these tissues such that they become unable to communicate properly with the immune system, and as a result induce improper and harmful rather than protective immune responses [18]. Evolution of the ‘danger’ model towards emphasizing the target tissues rather than focusing on signals I and II, adds another signal, for example a communication signal, to explain the efficacy of the immune response. However, attempts to describe the communication signal based on the ‘danger’ model prevent a full understanding of the communication between cells of the immune system and target tissues as noted in describing tissue-specificity of GVHD. According to the ‘danger’ model, the gut and the skin are more susceptible to GVHD following hematopoietic stem cell transplantation because they are most exposed to commensals and pathogens, which cause damage and induce danger [18]. However, the ‘danger’ model cannot explain a high incidence of GVHD following allogeneic, but not autologous transplantation. Neither can this theory explain the rejection of a foreign organ transplant and successful engraftment of an organ between identical twins, despite similar surgical procedures and tissue damage. future science group

The adaptation model of immunity

A successful kidney transplant in the identical Herrick twin brothers in 1954 suggests that tissue damage and injury do not always induce an effective immune response or graft rejection. Also, carcinomas are usually associated with local inflammation and tissue damage, yet an effective immune response is not always evident, even when peripheral tolerance is compromised by targeting Tregs or myeloid-derived suppressor cells (MDSC). Whereas the ‘danger’ model provides a better explanation for the induction of signal II, the ‘self–nonself’ model appears to have a better explanation for alloreactivity and tolerance of the graft from identical twins than ‘danger’ model does. Another challenge that the ‘danger’ model is facing is to explain the induction of pre-existing and ineffective immune responses to HER-2/neu, DNA or MBP without causing heart problem, lupus, or multiple sclerosis (MS), respectively. If endogenous ‘danger’ signals were involved in the induction of these immune responses, they cannot explain the efficacy of the immune responses.

Complexity of signal II The classical two-signal proposes that T-cell activation requires both signal I (antigen) and signal II (costimulation), and without signal II, T cells become anergic upon receiving the signal I. To this end, the T-cell costimulatory receptor CD28 is the most important molecule that interacts with B7‑1 and B7‑2 ligands on APCs in order to facilitate T-cell activation during antigen recognition. LFA-1 is another costimulatory molecule expressed on naive T cells and is upregulated (two- to four-fold) upon T-cell activation. Upon ligation with ICAM-1/2, LFA-1 lowers the threshold of T-cell activation. In the absence of LFA-1, 100-fold more antigen is required for T-cell–DC conjugation and all subsequent events of T-cell activation [20]. CD2 is also expressed on naive T cells, and upon ligation with LFA-3 it increases the avidity of T cells for target cells that express low levels of antigens [21]. In addition, the activated T cells begin to express the coinhibitory receptor cytotoxic T lymphocyte antigen 4 (CTLA-4) in order to inhibit an excessive activation of T cells. In fact, CTLA-4 has a greater affinity for B7 costimulatory molecules than CD28 does. This classical two-signal model suggests that costimulation regulates the activation and inhibition of T-cell function (Table 1). The signal II has already begun to evolve into a very complex regulatory system which exhibits more than just a stimulatory or an inhibitory function future science group

Perspective

on T cells. Emerging evidence suggest that each costimulatory or coinhibitory receptor is involved in different stage of T-cell responses, including T-cell activation, differentiation, effector function and survival (Table 2). For instance, ICOS, that was originally thought to promote Th2 differentiation also promotes Th1, Th17 and Tfh differentiation [22–25]. The costimulatory molecule CD28 not only support T cell survival following activation but it also supports maintenance of memory T cells as well as the recall response of CD8+ T cells to viral infections [26]. Similar function was reported for 4–1BB, OX40 and CD27 costimulatory molecules [27]. Importantly, many receptors are involved in the protection of T cells from activation-induced cell death (AICD) in order to modulate the effector function of T cells following activation (Table 2). For instance, engagement of 4–1BB/CD137 on T cells results in the upregulation of the antiapoptotic proteins c-FLIP and Bcl-x downstream of PI3K or the Akt/protein kinase B that also mediates CD28-induced inhibition of AICD [28]. There are also bidirectional cosignaling interactions between T cells and target cells or APCs when a costimulatory receptor engages with its coreceptor. For instance, engagement of B7‑1/B7‑2 on DCs with CTLA-4 on T cells induces the expression of indoleamine 2,3-dioxygenase in DCs [29], making them suppressive cells for T cells by the depletion of tryptophan, and directly inhibits T-cell response by the CTLA-4 signal transduction. The engagement of PD-1 on T cells with B7-H1 on cancer cells transduces inhibitory signals into T cells as well as antiapoptotic signals into cancer cells [30,31]. As previously unappreciated bidirectional cosignaling interactions continue to be identified, and multilevel functionality of costimulation is appreciated, a new classification is required to distinguish costimulatory/coinhibitory signals from those that are responsible for regulating the effector function of the immune response following antigen recognition (signal I) and activation (signal II); the signals that determine whether T cells or target cells will die or survive following their active interactions. Understanding and identification of such signals will revolutionize therapeutic approaches against cancer and autoimmune diseases.

Central tolerance: foreignness, danger or adaptation? A major question that both models are facing is why do mature T cells undergo apoptosis (negative selection) upon receiving signal I www.futuremedicine.com

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Table 1. Classification of costimulatory signals. Signal

T-cell receptor (type of T cell that expresses the receptor)

Function

B7-1/B7-2

CD28 (naive) CTLA-4 (activated)

Stimulation Inhibition

B7-H1 (PD-L1) B7-DC (PD-L2)

PD-1 (activated)

Inhibition

B7-H2 (ICOS-L)

ICOS (activated) CD28 CTLA-4

Stimulation Stimulation Inhibition

B7-H3

Unknown

Inhibition

B7-H4

Unknown

Inhibition

B7-H6

NCR3/NKp30 (activated)

Stimulation

CD70

CD27 (all T cells)

Stimulation

4–1BBL

4–1BB (activated)

Stimulation

OX40

OX40

Stimulation

GITRL

GITR (activated)

Stimulation

HVEM

BTLA (activated)

Inhibition

ICAM-1/2

LFA-1 (all T cells)

Stimulation

LFA-3

LFA-2 (CD2; all T cells)

Stimulation

LFA-1 DC-DESIGN

ICAM-3 (naive)

Stimulation

B7 family ligands/coreceptors

TNF family

Adhesion molecules

(self-peptides) and signal II (costimulation by mature DCs) in the thymus, but they survive and become effector cells in the periphery? Or how do recipients of allogeneic stem cell transplantation (SCT) develop central tolerance following the resolution of GVHD? Despite the differences, the ‘self–nonself ’ and ‘danger’ models share similar views on central tolerance, which include: ƒƒ Emphasis on signal I to explain positive and negative selections in the thymus; ƒƒ The notion that positive and negative selections of T cells are present in neonates and children but they are not efficient in adults and the elderly [32]. These concepts need to be revisited in order to advance our understanding of the decision-making process during the immune response. Positive selection determines MHC restriction and results in the maturation of CD4+CD8+ T cells into CD4+ or CD8+ T cells by MHC class II or MHC class I recognition, respectively. During positive selection, MHC/self-peptide complex (signal I) selects and supports survival of only T cells that are self-reactive, whereas all 62

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T cells that fail to recognize self-antigens are eliminated by apoptosis. Eliminated T cells could be potentially reactive towards nonself-antigens. During positive selection, T cells should also prepare themselves for negative selection such that they survive complete elimination and also do not kill APCs upon activation. In fact, T cells should be able to upregulate the expression of antiapoptotic genes upon activation and also transduce survival signals in DCs during their interaction so that DCs can survive cytotoxic function of CD8+ T cells. Only 3–5% of T cells survive the positive selection. Positively selected T cells in the cortex of the thymus will then move to the medulla to undergo negative selection. The tissue-restriction of positive and negative selections in the cortex and the medulla, respectively, suggest that different communication signals are involved in the thymus. During negative selection, T cells should be able to recognize only nominal self-antigens towards which they were positively selected. The question is, why do T cells that recognize selfMHC antigen survive during positive selection, but die during negative selection? According to the ‘avidity hypothesis,’ avidity of antigen future science group

The adaptation model of immunity

recognition during negative selection is higher than that in positive selection so as to cause AICD in T cells [33]. Such an increased avidity of T cells is due to the presence of mature DCs in the medulla providing signal I (self-antigens) and signal II (costimulation) for T cells [34–36]. Medullary thymic epithelial cells (mTEC) are unique APCs in that they express AIRE genes, which promote expression of a wide array of tissue-specific antigens (TSAs) [37–39]. mTEC become efficient at negative selection of T cells because they express costimulatory molecules such as CD40, B7‑1 and B7‑2 (signal II) [40–42]. In addition, cross-presentation of mTEC-derived TSA by medullary DC can occur to promote clonal deletion of T cells [43,44]. During negative selection, T-cell activation will result in AICD in some but not all self-reactive T cells. Those T cells that survive during negative selection are in fact the ones that will not commit suicide upon activation. In addition, these T cells will not kill APCs during activation in the secondary lymphoid tissues. Given that all positively selected T cells that encounter APCs recognize nominal self-antigens in the medulla, they all must have comparable avidity for the antigen during the negative selection. Accordingly, avidity for signal I is unlikely the determinant of clonal deletion of T cells. For instance, AIRE deficiency does not affect TSA gene expression (signal I), but it still affects negative selection of T cells and results in multiorgan autoimmune disease which involves ovarian and testicular failure [42,45,46]. The ‘danger’ model cannot explain the maturity of DCs during negative selection and elimination of T cells upon activation, because these physiological events take place in the absence of ‘danger’. However, adding the communication signal III to the picture, independent of signals I/II and danger signal,

Perspective

provides an explanation for these phenomena. To this end, such communication has to be regulated through adaptation by expressing adapting receptors (AR) and adapting ligands (AL) on cells of the immune system and other somatic cells such that these cells can continue to have harmless communications with each other, even during the immune response. According to the ‘adaptation’ model, survival of T cells and mature DCs during negative selection in the thymus is because of the engagement of AR/AL. Those T cells that do not express AR will die upon activation (negative selection). This model can also explain tolerance during an ongoing immune response. For instance, normal tissue homeostasis takes place by apoptotic cell death that sometimes is immunogenic. It was recently shown that during immunogenic apoptosis, but not mitochondrial apoptosis, caspases regulate membrane translocation of the lysosomal protein LAMP1 and facilitate redistribution of ATP from lysosomes to autophagolysosomes and its secretion as an inducer of the immune response [47]. In addition, the immunogenic ATP release requires the opening of PANX1 channels, which are triggered by caspases [47]. This suggests that without a dangerous death or necrosis, an immune response can be elicited by physiological apoptosis. Thus, tissue must have developed an adaptation mechanism in order to protect itself from the ongoing immune responses. In fact, tolerance is regulated via engagement of the AR/AL during the tissuespecific immune responses to guarantee that ongoing immune responses do not harm the host. This possibility is also supported by the detection of pre-existing immune responses against self-proteins without causing autoimmune diseases as well as ineffective immune responses against cancer following vaccination.

Table 2. The role of costimulatory molecules during the immune response. Molecule

Activation

Survival

Differentiation

Effector

Memory

CD28

+

+

ND

ND

+

ICOS

ND

+

Th1/Th2/Th17/Tfh

+

+

HVEM

+

+

ND

+

+

CD27

+

+

Th1

+

+

4–1BB

ND

+

ND

+

+

OX40

ND

+

Th9

+

+

CD2

+

ND

ND

+

+

DNAM-1

ND

ND

CD8

+

ND

+: Yes; ND: Not determined.

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Table 3. Three signals during immune responses. Signal

Function

I

Recognition of self or nonself mimic of self by T cells

II

Activation of the immune response

III

Efficacy of the immune response

Biological systems survive based on adapt­ ation to the environment over a period of time. Therefore, it is reasonable to postulate that all cells in the body have the ability to express AR and AL, which modulate adaptive immune responses beyond signal I (antigen recognition) and signal II (costimulation). In this model, T cells require an adaptation signal or signal III (AR/AL) to overcome AICD (Table 3). Upon engagement with AL on target cells, AR transduce signals for the expression of antiapoptotic proteins, such as cFLIP and Bcl-xL, during T-cell activation [48]. Lack of expression of AL by APCs could result in AICD in T cells. For instance, hepatic DCs induce apoptosis in T cells following activation, whereas splenic DCs support survival of activated T cells [49]. According to the ‘adaptation’ hypothesis (Figure 1), target tissues or cells must be altered to lose the expression of AR in order to undergo apoptosis upon recognition by activated T cells. Tissue specificity in autoimmune diseases is due to such alterations in target tissues, rather than changes in signal I or II. For instance, T cells that recognize MBP are detected in patients with MS as well as in healthy individuals [50,51]. In fact, both autoreactive T cells and tolerant T cells can recognize similar signals I and II, but they react differently because of signal III (AR/AL). Similar observations were made in healthy individuals and patients with lupus erythematosus who harbor anti-DNA autoantibodies with pathogenic manifestation only in the latter [52,53]. Whereas Th1 and Th17 inflammatory cells in the gut can protect the host from Helicobacter pylori infection without any toxicity [54], they become destructive during Crohn’s disease. These paradoxical observations suggest that Th1 or Th17 cells are not primary factors in the pathogenesis of Crohn’s disease; rather, the altered gut tissue that fails to control Th1 response or adapt to the inflammatory response is the primary factor. To this end, commensal gut bacteria that are involved in intestinal homeostasis perhaps regulate the expression of AR in the gut. In fact, an altered gut microbiome profile was shown to be associated with 64

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Crohn’s disease such that nutritional therapy can modulate pediatric Crohn’s disease [55]. The intestinal tissue alterations can be induced by epigenetic changes as a result of changes in the gut flora which in turn result in the loss or downregulation of AR in the intestinal cells, rendering the tissue susceptible to inflammatory response. Similarly, infiltration of inflammatory immune cells and CD8+ T cells in patients with colorectal cancer are associated with a better prognosis without inducing severe autoimmune disease in the gut [56]. Any alterations in the engagement of certain AL on activated T cells with the nominal AR on target cells would result in tissue-specific autoimmune reactions upon antigen recognition, which is also the case during GVHD. Therefore, GVHD in some, but not all, patients following allogeneic SCT may be due to alterations in signal III in certain tissues rather than the nonself entity of signal I or damage-associated danger signals. In fact, preconditioning regimens during allogeneic SCT may alter the expression of AR on certain tissues, rendering them susceptible to GVHD. Similarly, alterations in the expression of AR in a grafted tissue may result in the graft rejection. There may also be individual variations in the expression of AR/AL that make a successful engraftment between identical twins possible. Moreover, the GVHD, following SCT, or host-versus-graft effect following solid organ transplantation occurs because donor-recipient pairs are selected based on their match in signal I and not in signal III. Accord­­ingly, failure in the rejection of autologous graft or lack of GVHD following autologous SCT could be due to the presence of an intact signal III that was adapted during central tolerance in the recipient. However, when viruses, such as influenza, alter signal III in target tissues, an effective immune response would follow. Viruses that fail to alter signal III would survive because of the established adaptation between the host cells and cells of the immune system, despite the expression of nonself viral proteins in the context of signal I. Clinically asymptomatic HIV infection, dormant TB [57] or dormant and quiescent tumor cells [58] are indicative of the ability of the immune system to adapt to life-threatening insults and contain but not destroy them. These observations suggest that efficacy of the immune response is not merely determined by the antigen (signal I) or damageassociated danger signals caused by a viral infection, which can induce signal II. Alterations in the expression of AR and AL as a result of epigenetic modifications or somatic mutations can result in autoimmune diseases, allergic reactions, future science group

The adaptation model of immunity

rejection of solid organ transplant, and spontaneous regression of cancer. In fact, rejection of a matched cadaver donor kidney but engraftment of an unmatched live donor kidney is not due to the foreignness of the graft, but rather owing to alterations in AR/AL machinery in the cadaver donor kidney. Therefore, identification of AR and AL, as well as mechanisms by which they are regulated, can result in a breakthrough in our understanding of the immune system, and in the development of therapeutic strategies for human diseases.

What are adaptation signals? Identification of numerous costimulatory molecules has improved our understanding of the immune response. Many of these molecules act beyond activation of T cells (signal II), some of which are involved in inducing anti-apoptotic genes when encountering the immune response; thus, a new classification is needed to identify receptors that are responsible for the communication between somatic cells and cells of the immune system. Three important costimulatory molecules that are induced following T‑cell activation and regulate T‑cell suppression are: CTLA-4, PD-1 and BTLA. Among these inhibitory receptors, PD-1 plays a unique role in the communication of T cells with other somatic cells. There are two ligands/coreceptors that interact with PD-1. These include B7-H1 (PD-L1), which is expressed in almost all somatic cells, and B7-DC (PD-L2), which is expressed on activated DCs. IFN-g produced by effector T cells upregulates the expression of PD-1 and B7-H1/B-7DC. Upon the PD-1/B7-H1 engagement, a bidirectional signaling will follow. B7-H1 relays downstream signals for the induction of antiapoptotic proteins to survive the T-cell attack, and PD-1 relays signals in T cells to suppress their effector function or facilitate T-cell deletion. In fact, constitutive expression of B7-H1 facilitate the cellular adaptation to the attack by an ongoing immune response. B7-H1 is expressed in the thymic cortex and medulla, whereas B7-DC is expressed on medullar DCs [59,60], suggesting their role in positive and negative selections. The expression of B7-H1 in placenta was also reported, suggesting its regulatory role during fetus tolerance [59,61,62]. Expression of B7-H1 has also been reported in malignant cells to support tumor cell survival from T cell responses; blocking the PD-1/B7-H1 pathway thus demonstrates a promising strategy for cancer therapy [63]. These observations suggest that B7-H1 is an AR constitutively expressed on future science group

T cells

Target

Perspective

Outcome

• T-cell survival upon activation • Containment of target cells or tumor dormancy

• Tissue-specific autoimmune diseases • GVHD • Rejection of solid organ transplant • Spontaneous regression of cancer

• AICD in T cells • Graft failure following allogeneic SCT • Negative selection

• Multiorgan GVHD

AL

AR

Figure 1. Adaptation model of immunity. Depicts how adaptation can determine different types of the immune responses when signals I and II are present. (A) Expression of AR on T cells and AL on target cells or tissues leads to T-cell survival upon activation during the immune response, whereas expression of AR on target cells and AL on T cells results in the survival but containment of target cells, that is, tumor dormancy. (B) AR and AL is expressed on activated T cells, but any alterations in the expression of AR on target tissues lead to the induction of tissue-specific autoimmune diseases, tissue-specific allergic reactions, GVHD, rejection of solid organ transplant or spontaneous regression of cancer. (C) Alterations in AR expression on activated T cells lead to AICD, graft failure or clonal deletion of T cells during negative selection in the thymus. (D) Loss of AL on activated T cells may result in multiorgan acute GVHD. AICD: Activation-induced cell death; AL: Adapting ligand; AR: Adapting receptor; GVHD: Graft-versus-host disease; SCT: Stem cell transplantation.

cells to protect them from the ongoing immune responses. For instance, constitutive expression of B7-H1 in the immune privileged sites such as cornea and retina protect these areas from GVHD following corneal allograft, despite infiltration of CD4+ T cells; however, blockade of B7-H1, but not B7-DC, resulted in an accelerated allograft rejection [64]. In a murine model, B7-H1 deficiency in pancreatic b‑cells triggers pancreatic b-cell destruction by CD8+ T cells [65]. An altered expression of B7-H1 correlates with not only autoimmune diseases, but also HIV infection and cancer progression. For instance, loss of B7-H1 expression has been reported in children with systemic lupus erythematosus, and expression of this protein was detected only during disease remission [66]. www.futuremedicine.com

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B7-H1 is also upregulated in HIV infection associated with a low CD4 count, and antiviral therapy results in downregulation of B7-H1 expression [67]. These observations suggest that upregulation of B7-H1 protects HIV-infected cells and eliminates the PD-1-positive virus-reactive T cells. The PD-1/B7-H1 pathway has also been shown to be involved in cancer progression [68]; importantly, a very recent report at the American Society of Clinical Oncology meeting suggested that targeting B7-H1 pathway can generate promising results in the treatment of melanoma [69]. AIRE is another important gene that may be involved in regulating the communication between T cells and target tissues. AIRE deficiency does not affect the TSA gene expression (signal I), but it still affects negative selection of T cells and results in multiorgan autoimmune disease which involves ovarian and testicular failure [42,45,46]. These observations suggest that signal I is not critical for the thymic negative selection, and that AIRE is involved in the regulation of the expression of AR in the thymus. We know that AIRE interacts with an unexpectedly large number of binding partners including proteins involved in transcription, nuclear transport, and chromatin binding and structure [70]. Tissues that fail to express AR will be vulnerable to the immune response and autoimmune diseases, or T cells that fail to express AR to interact with AL on APCs will not receive survival signal and are eliminated upon receiving signals I and II during activation. Both constitutive expression and induced expression of AR may be involved in the regulation T-cell selection and their communication with other cells and tissues.

Latent infections may modulate AR expression in a tissue-specific manner & account for the success or failure of solid organ transplantation & treatment of autoimmune diseases In addition to the constitutive expression of AR, its induced expression or loss of expression may also occur. To this end, infectious agents such as Mycobacterium tuberculosis that can cause a dormant or latent infection may modulate the expression of AR in the infected cells. In individuals with latent M. tuberculosis, the immune system can only control and inhibit the growth of the bacteria rather than eliminating the infected cells. Over 30% of people worldwide harbor a latent or dormant form of M. tuberculosis. TB usually affects the lungs, but it can also affect the brain, spine and kidneys. Upregulation of 66

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AR by M. tuberculosis may be responsible for inability of the immune response to eliminate the infected cells. Also, modulation of AR expression in the kidneys of donors who harbor latent M. tuberculosis may be responsible for the highest rates of successful kidney transplantation in spite of using less immunosuppression compared with other organ transplantations. Interestingly, kidney transplantation is associated with greater risk of TB. In fact, post-transplant immune suppression regimen results in reactivation of latent M. tuberculosis and clinical form of the disease. If atypical or latent M. tuberculosis can modulate AR expression in the kidney, a successful kidney transplant should be evident even without immune suppression. In this case, M. tuberculosis will remain latent in the recipient of organ transplant. While both the kidneys and the lungs can harbor latent M. tuberculosis, why are kidney transplantations highly successful whereas lung transplantations have the poorest survival rate among solid organ transplants? This could be due to tissue-specific modulation of AR by atypical or latent M. tuberculosis. Different epigenetic regulatory pathways for the expression or loss of AR in different tissues may also account for tissue-specific autoimmune diseases. Another implication for M. tuberculosis-induced modulation of AR is the treatment of autoimmune diseases. For instance, M. tuberculosis infection results in the resistance of mice to experimental autoimmune encephalomyelitis [71–73]. In fact, a 12-kDa HSP of M. tuberculosis can protect mice against experimental autoimmune encephalomyelitis [74]. In patients with MS, adjuvant therapy with BCG has been shown to be a promising strategy [75]. Very recently, this strategy has also been tested for the treatment of long-term Type 1 diabetes [76]. Such promising effects are not likely due to immunogenicity of M. tuberculosis antigens, because T cells reacting with MBP are already present in both MS patients and healthy individuals [29,30], although they do not cause MS in healthy individuals. In fact, expression of AR in target cells and tissues may be responsible for the efficacy of M. tuberculosis and BCG in the treatment of autoimmune diseases or the management of solid organ transplantation.

Central tolerance in the elderly The concept that central tolerance is absent in the elderly due to thymic involution needs to be revisited. Allogeneic SCT has been shown to be successful for many patients with hematological malignancies, including the elderly. This is not solely due to the peripheral tolerance, since a future science group

The adaptation model of immunity

new rearrangement of T-cell receptors is evident in the elderly following allogeneic SCT. In fact, patients that harbor full chimerism of the donor T cells show unique TcR Vb that are not detectable in the donors [M anjili M et al., Unpublished Data]. In addition, lack of alloreactivity of the donor-derived T cells with foreign antigens in the recipients who did not develop GVHD suggests the presence of central tolerance in adults. In the absence of active thymus in the elderly, extrathymic T-cell maturation is responsible for central tolerance as reported by other groups [31,77]. Presence of central tolerance throughout life can also explain phenomenon such as, acquisition of central tolerance to new fetus, as well as newly lactating breast tissue. Development of central tolerance was previously postulated in a 42-year-old female who received allogeneic bone marrow transplant and was concurrently infected with HCV from an HLA-DR11+ donor sibling [78]. An acute HCV infection developed and was treated, although the recipient showed a selective lack of HCV-specific T cells and absence of antibody response compared with the treated donor. The authors postulated that introduction of viral antigen during maturation of a donor’s T cells in the recipient induced acquired central tolerance. Therefore, central tolerance should be thought of as an ongoing process throughout life in order to protect individuals in a dynamic environment.

Future perspective Signal II that was initially conceived as a costimulation required for T-cell activation has now expanded beyond just T-cell activation. Many costimulatory molecules are

Perspective

being discovered and many of them are not just involved in T-cell activation, rather they are involved in T-cell differentiation, effector function or survival and adaptation. It is time to propose a new classification that can distinguish receptors that regulate ‘adaptation’ or tolerance of the ongoing immune responses. Emerging evidence suggest the presence of selfreactive immune responses toward HER-2/neu, DNA or MBP without causing autoimmune diseases, unless target tissues become defective in their adaptation to the immune response. The adaptation model suggests a new angle for understanding of the immune system by focusing on how an immune response becomes effective or ineffective rather than on how an immune response is induced, which in most cases is ineffective for cancer therapy. The ‘adaptation’ model could facilitate discovery of new molecules that are constitutively expressed or induced in somatic cells, and are responsible for the efficacy of the immune response. Acknowledgements The author gratefully acknowledge the support of VCU Massey Cancer Center and the Commonwealth Foundation for Cancer Research.

Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Executive summary ƒƒ The ‘self–nonself’ theory explains the rejection of a foreign organ or acceptance of an organ between identical twins, but it cannot explain variations in the immune response toward self or nonself proteins without relying on the factors that are independent of the antigenic determinant, such as costimulatory signals and peripheral tolerance. ƒƒ The ‘danger’ theory provides a better explanation for the induction of costimulatory signals induced by damaged cells or danger during T-cell activation. However, it cannot explain graft-versus-host disease following an allogeneic, but not an autologous, stem cell transplantation; neither can it explain the rejection of a foreign organ and acceptance of an organ between identical twins. ƒƒ Immunological tolerance in the presence of foreign proteins or danger signals, as well as the immune response to self or in the absence of danger, cannot be explained by the ‘self–nonself’ or ‘danger’ models. These suggest that decision-making during the immune response is not solely determined by ‘nonself’ entity of the antigen or damage-associated ‘danger’ signals. ƒƒ While signal I (antigen presentation) and signal II (costimulation) explain the induction of an immune response, signal III (adaptation) explains the efficacy of an immune response ranging from tolerance to elimination of target cells. ƒƒ The ‘adaptation’ model suggests that communication between cells of the immune system and all other somatic cells is regulated through ‘adaptation’ by expressing adapting receptors (AR) and adapting ligands in order to guarantee a harmless communication, even during the immune response. The AR are either constitutively expressed or induced by epigenetic changes in the cells. ƒƒ Any alterations in the expression of AR on certain tissues would result in tissue-specific autoimmune diseases or spontaneous regression of cancer.

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