M in i Review Int Arch Allergy Immunol 1992:99:1-7

Section of Clinical Immunology, University Hospital, Zürich. Switzerland; and Department of Neurology, Klinikum Grosshadern. University of Munich, FRG

Key Words Transforming growth factor |i Immunosuppression Autoimmunity Brain tumors Inflammation Cytokines

Modulation of the Immune Response by Transforming Growth Factor Beta

Abstract For the past several years immunologists have been fascinated by a series of ex­ periments showing that transforming growth factor (5 (TGFJI) suppresses Tand B-lymphocyte growth as well as IgM and IgG production by B cells. More­ over, while exerting chemotactic activity on monocytes and inducing expres­ sion of interleukin-1 and interleukin-6 by these cells, TGFp interferes with bacterially induced tumor necrosis factor a production, oxygen radical formation and the adhesiveness of granulocytes to endothelial cells. These mechanisms may provide the basis for the effect of TGF(! to prevent the microvascular changes associated with brain edema formation in bacterial meningitis. Given the potential of lymphocytes as well as macrophages to produce TGF|11. this cytokine may exert negative feedback signals on the immune response, pro­ vided the cytokine is processed from its latent form to the bioactive homodimer. Potent effects of TGF|1 have been observed in experimental animals in­ cluding the inhibition of the generation of virus-specific cytotoxic T cells and antiviral antibodies as well as the diminution of cellular infiltrates with de­ creased major histocompatibility complex class-II expression and CD8+ T cells in the tissue of virally infected animals. TGF(i may also be of importance in tu­ mor immunology. By the production of bioactive TGF(i as detected in glioblas­ toma and acute T-cell leukemia, tumor cells may induce an immunodeficiency state and escape immune surveillance. In inflammation, monitoring of TGFfl in the tissue will bring light on the immune regulation in acute and chronic in­ flammatory diseases.

The role of lymphocytes and monocytes in the regu­ lation of the immune response is the subject of much in­ vestigation. Purification and cDNA cloning revealed sev­ eral novel immunosuppressive cytokines including the macrophage-derived intcrlcukin-1 receptor antagonist (IL-lra) and IL-10, the latter suppressing major histocom­ patibility complex (MHC) class-II and cytokine expies-

sion. Furthermore from the studies on cytokine receptors, e.g. IL-2, IL-6 and tumor necrosis factor a (TNFa) recep­ tors, it became evident that a soluble form of such proteins exists, which may compete with the respective membrane receptors for ligand binding. Recently, T-cell growth regu­ latory molecules have been recognized as secretory prod­ ucts of T lymphocytes and characterized as transforming

This work was supported by the Swiss National Research Foundation (31.28402.90).

Correspondence to: Or. Adriano Fontana Section of Clinical Immunology University Hospital I laldeliweg 4 Cl 1-8044 Zurich (Switzerland)

© I992S. Karger AG. Basel 1018-2438/92/0991-0001 $ 2.75/0

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A. Fontanaa D.B. Constant;1 K. Frei3 U. Malipieroa //.IT Pfisterb

TGF[i Inhibits T-Lymphocyte Growth and Immunoglobulin Production by B Cells The immunosuppressive property of TGF[1 was de­ tected for the first time in studies on the characterization of a glioblastoma-derived T-ccll suppressor factor [16]. When added to CD4 or CD8 positive T-cell clones, the glioma-derived factor, which after its cDNA cloning was termed TGFJ12, completely suppressed the proliferative response of the T cells to IL-2 or phorbol cstcr/ionophorc [16], Furthermore. TGF[) blocked the generation of both cytotoxic T cells in allogeneic mixed lymphocyte cultures and IL-2-induced Iymphokine-activated killer cells and natural killer cells [16]. Immunosuppression on a murine MHC class-II-restriced T-lymphocyte clone was mediated by TGF|11, (12, and [13 [17] but not by other members of the TGF[1 family, namely inhibin and BMP-2 [unpublished ob­ servation], As suggested from epithelial cells, TGF(1 may interfere directly with the cell cycle in late G1 by inhibiting phosphorylation of the retinoblastoma protein, which in the absence of exogenously added TGF() is detected in the hyperphosphorylated form in the S and G2/M phase [18], However. T-cell growth is also regulated by TGF|1 in an in­ direct pathway involving TGFfl-induced production of IL-lra, which competes with IL-1, the second signal re­ quired in the activation of T-helper cells [19]. In addition. TGF|1 blocked phytohemagglutinin-induced interferon y


(IFNy) production by T lymphocytes, as well as causing in­ hibition of IL-2 and IFN« receptor expression [20]. Thus, TGF[$-depcndenl suppression of antigen-induced T-cell growth involves several distinct pathways. On B cells, TGF(i is growth inhibitory and interferes with the acquisition of the k light chain by murine pre-B cells and the secretion of IgM and IgG by activated B lym­ phocytes [21, 22], On the RNA level, TGF(I reduces the light chain as well as the p heavy chain expression and, most importantly for the overall inhibition of immuno­ globulin secretion, TGF(I interferes with the switch from the membrane forms to the secreted forms of p and y heavy chains [23]. In contrast, TGFfl enhances isotype switching to IgA [24],

Immunosuppression by TGF|] in vivo The availability of recombinant TGF|11 and (12 allowed an in vivo approach to investigate the potential immuno­ suppressive properties of the respective cytokines. The function of TGF|i in vivo was not readily predictable be­ cause «2-macroglobulin (a2M), a serum protease inhib­ itor, has been found to interfere with the ability of TGF[5 to abrogate the growth-inducing effect of IL-2 on T-cell lines [25]. Inactivation of TGFfl may be due to formation of a TGF(V«2M complex; in addition cx2M also competes for 125I-TGF|) high-affinity binding to its cell surface recep­ tor. TGF[5 eomplexed to a2M has been described in hu­ man serum [for references sec Fontana et al., 26]. It re­ mains to be seen whether rTGF() eomplexed with «2M is still bioactive or whether the complex dissociates at rele­ vant target sites in vivo. The immunoregulatory effects of TGF|31 and (32 were first assessed in mice infected with lymphocytic chorio­ meningitis (LCM) virus or vaccinia virus. Starting on the day of infection, intraperitoneal injections of 1 pg/day of recombinant TGF|S1 or TGF|!2 suppressed the generation of virus (Vaccinia or LCMV)-specific cytolytic T lympho­ cytes [26], Since LCMV-specific class-I MHC-rcstricted cytotoxic T cells have been shown to be essential for the clearance of virus, the development of disease and for the delayed-type hypersensitivity-like inflammatory reaction in infected footpads, these parameters were also eval­ uated in TGF(i-treated, LCMV-infccted animals. Indeed TGF|I significantly prolonged the survival interval after LCMV infection, inhibited the footpad swelling after local LCMV injection and impaired clearance of LCMV in in­ fected mice [26], Since MHC class-I-restricted cytotoxic T cells predom­


Immune Regulation by TGF|i

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growth factor (I (TGF(I). The TGF|I superfamily comprises an increasing number of structurally related proteins in­ volved in morphogenetic and developmental events. The prototype of this family is TGFfll which originally was pu­ rified from human platelets and found to be a disulfidelinked homodimer of the C-tcrminal 112 amino acids de­ rived from a 390 amino acid precursor peptide [1]. Five members of the TGF[i superfamily, called TGF(U to |35, ex­ hibit 65-80% sequence homologies to each other and share nine conserved cysteine residues involved in intraand interchain disulfide bond formation. TGF[I1 to [13 have been cloned in mammals so far [2-4], whereas TGF[i4 and |)5 have been found only in chick and xenopus, respec­ tively [5. 6], Members of the TGF(I superfamily showing less structural homology to TGFjll are the bone morpho­ genetic proteins (BMP) BMP-2 (or BMP-2A). BMP-3 (or osteogenin), BMP-4 (or BMP-2B) [71, BMP-5, BMP-6 (or vgr-l/OP-1) and BMP-7 [8—10], the product of the decapentaplegic complex of Drosophila [11], the inhibins [12], Mullerian inhibiting substance [13], the vegetal pole-spe­ cific transcript of xenopus, vg-1 [14], and GDF-1 [15],

The results in EAE and Borna disease prompted in­ vestigations on TGF[5 secretion by glia cells of the nervous system. Reduced expression of TGF|i in the tissue may lead to impaired local control of the immune response in brain parenchyma. Astrocytes arc facultative antigen-pre­ senting cells and secrete TGF|J2 in a latent form [17]. This contrasts microglia, the tissue macrophages of the nervous system, which produce latent TGFpi. No difference in ex­ pression of TGF[) was noted when comparing glia cells of brown Norway rats to those of Lewis rats, two strains known for their different susceptibility to EAE [17]. Al­ though alterations in expression of TGF[5 are unlikely to be the cause of genetic differences in EAE susceptibility, TGF(1 produced by parenchymal cells such as glia cells in the nervous system may influence immune reactivity in the tissue. The Borna disease model was found to be especially useful to investigate the effect of TGFp on B lymphocytes. As expected from in vitro studies, infected animals treated with TGFp showed a striking reduction in the production of anti-viral antibodies (mostly IgG). Both the effects of TGF() on T and B lymphocytes were not paralleled by a re­ duction in synthesis of virus-specific proteins and infec­ tious BV in the brain [29], Taken collectively, the experience with TGFp on the LCMV, BV model and on EAE clearly documents the im­ munosuppressive effects of TGFp, but does not give an an­ swer on the precise way of action of TGFp. Given the pleiotropic function of TGFp in vitro to inhibit IFNy pro­ duction, to downregulate MHC ciass-II and IL-2 receptor expression, to interfer with immunoglobulin synthesis and expansion of antigen-specific cytotoxic T cells and T-helper cells, it is fair to state that TGFp acts also in disease models on very different immune circuits. W hereas there was no evidence for TGFp to induce immune tolerance, only incomplete and temporary effects of TGF[1 being noted, a recent report has connected TGFp with induction of oral tolerance in rats. When tolerized to myelin basic protein a marked reduction in severity and duration of EAE can be observed. However, in vivo treatment with anti-TGFpi antiserum abrogated the protection induced by oral administration of myelin basic protein [32], The precise mechanisms of both oral tolerance and the in­ volvement of TGFfS in it, are certainly fascinating to study.


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inate in the pathogenesis of LCMV disease, it seemed worthwhile to us to extend the studies on TGF[1 on an ex­ perimental disease thought to depend on virus-specific CD4+ T cells. Borna disease is a sporadically occurring progressive encephalopathy of horses and sheep, and can be induced experimentally in a wide range of animal spe­ cies by infection with Borna virus (BV), a single-stranded RNA virus. The pathogenesis of disease includes an im­ mune component since cyclosporin A-treated BV-infected adult rats lack virus-specific T cells as well as encephalitic lesions in the nervous system [21]. However, the disease can be transmitted by adoptive transfer of CD4+ T cells from Borna-discascd animals to cyclosporin A-lreatcd in­ fected recipients [281. TGFp also modulates Borna disease in experimental animals. Intraperitoneal injection of rTGF(12, started on the day of infection at a dose of either 1 ¡.tg given every day or every other day for 8 consecutive days or 2 pg every 3rd day, was found to result in the ab­ sence of typical Borna disease symptoms at 14 days after infection in most of the TGFp-trcated rats, a time point at which all infected control animals not treated with rTGF[52 showed distinct signs of Borna disease [29], The inhibition of the disease was paralleled by a significant re­ duction in the inflammatory reaction in the brain. The number of brain tissue-infiltrating cells was reduced, with a most dramatic reduction in CD8+ T cells and much less so of CD4+ T cells, the number of ED1 + macrophages not being different. Furthermore, a clear inhibition of MHC class-11 expression was noted in the brains of TGF|)2treated BV-infected rats [29]. However, the efficacy of treatment with rTGF[12 was transient, because after day 21 only a slight or no reduction in the inflammatory reaction and. consequently, symptoms of Borna disease could be observed. It is not yet known whether continuation of TGF|1 treatment influences disease outcome on a long­ term basis or whether an escape phenomenon due to loss of TGFp receptors on T cells (sec below) will occur. Inhi­ bition of T-cell-mediated disease by TGF()1 has also been shown in experimental allergic encephalitis induced by adoptive transfer of myelin basic protein-specific MHC class-II-restricted T cells in SJL mice [30], In TGF|1treated animals, only sparse inflammation with a reduc­ tion in inflammatory cells in the infiltrates and decreased expression of MHC class II as well as LFA-1 was noted [30], However, TGF(1 injected intraperitoneally daily dur­ ing the first 2 weeks after active immunization of SJL mice with myelin basic protein delayed, but did not suppress, development of acute experimental allergic encephalo­ myelitis (EAE) [31], Treatment after the first attack of EAE prevented spontaneous relapses of the disease [311.

An anti-inflammatory effect of TGFp can be shown in experimental meningitis. Rats inoculated intracisternally with live pneumococci or with pneumococcal cell wall hy­ drolyzed by the Ml muramidasc develop within 1-3 h an increase in cerebral blood flow and intracranial pressure with brain edema formation [33], These changes are all in­ hibited by a single intraperitoneal injection of TGFpi or (32 (1-10 pg) [34], The pathway involved in the prevention of pathologic events in bacterial meningitis by TGFp has not yet been established. The potent effect of TGFp to block TN Fa production by lipopolysaccharidc (LPS)-treated peritoneal macrophages in vitro [35] seems not to be cru­ cial in the meningitis model since intraperitoneal or intracerebrospinal fluid injections of anti-TNFa antibodies failed to mimic the effect observed with TGFp [34]. This is of note since TNFa is produced in the central nervous sys­ tem in bacterial meningitis and induces pleocytosis when injected into the cerebrospinal fluid compartment of ex­ perimental animals [36,37], TGFp may interfere with early endothelial changes induced by bacteria and/or granulo­ cytes, a process which may involve oxygen radical interme­ diates. This is supported by the recent observation of superoxidc dismutase, a scavenger of oxygen-derived free radicals, to attenuate the development of microvascular changes in the early phase of experimental meningitis [33]. TGFp also inhibits formation of radical oxygen intermedi­ ates and the release of nitric oxide by activated macro­ phages [38], Moreover, TGFp has been found to induce production and secretion of the IL-lra by human blood monocytes [19]. IL-lra blocks IL-l-induced fever, hypoten­ sion, neutrophilia and locally IL-l-induced inflammation [39]. With regard to the findings in experimental meningi­ tis, it is also interesting that under culture conditions en­ dothelial cells show only limited leukocyte adhesiveness in the presence of TGFp [40]. The data outlined above point to an anti-inflammatory action of TGFp. Nevertheless, the opposite view has also been stated due to the observation of TGFp to augment various functions of monocytes: TGFp is strongly chcmotactic, induces FcRIII (CD16) and leads to enhanced ex­ pression of IL-1 and 6, of platelet-derived growth factors and basic fibroblast growth factor [for references see Wahl, 411. By these properties TGFp may provide an im­ portant induction signal to the role of monocytes to regu­ late growth and function of fibroblasts, a process consid­ ered to be essential for the development of wound healing and fibrosis. Tissue repair is also promoted by the angio­


genic effect of TGFp. Intra-articular injections lead to swelling and erythema of injected joints within 1-2 days [42], In association with the development of infiltrates, composed predominantly of mononuclear phagocytes, was an increase in synovial fibroblast-like cells and an an­ giogenic response. In contrast to collagen-induced arthri­ tis, the TGFp-mediated synovitis resolved spontaneously without destruction of cartilage and bone [42]. On one hand TGFp has proinflammatory activities when injected intra-articularly, on the other TGFp protects from the de­ velopment of T-cell-dependent arthritis induced by immu­ nization with collagen or by injection of peptidoglycanpolysaccharide fragments [31, 43], Thus in immune-mediated diseases like Borna disease, LCMV disease, EAE and T-cell-mediated arthritis, TGFp, by its immunosuppres­ sive activity, is an anti-inflammatory agent. Nevertheless, inflammation can be induced by TGFp injected locally, the process triggered being, however, of a self-limited extent [42]. This may be due to the capacity of TGFp to recruit anti-inflammatory processes such as induction of the IL-lra. While enhancing the function of monocytes TGF|1 rather inhibits the proinflammatory role of differentiated macrophages.

Is There an Autocrine Role for TGFp Produced by Lymphocytes and Macrophages? With the exception of glioblastoma, TGFps are se­ creted by most primary cells in culture and by long-term cell lines in the latent form (L-TGF[3) that does not inter­ act with specific TGFp cell curface receptors. This holds also true for activated T and B lymphocytes as well as mac­ rophages which all express TGFpi mRNA and secrete TGFpi in the latent form [20, 21, 44]. Nonactivated T and B cells produce very low levels of TGFpi. In contrast hu­ man T-cell leukemia virus-infected T-cell lines and freshly isolated leukemia cells from patients with acute T-cell leu­ kemia secrete levels of TGF|1 equivalent to and/or in ex­ cess of mitogen-activated lymphocytes. In T-cell leukemia cells AP-l-binding sites present in the TGF(51 (but not TGF|32) promoter are activated by the T-cell leukemia virus-I-encoded Tax protein [45,46]. The excessive produc­ tion of TGFpi maybe important in the pathogenesis of im­ mune suppression and hypercalcemia associated with acute T-cell leukemia. Provided activation of L-TGF|1, its secretion by lym­ phocytes and macrophages may provide a negative feed­ back signal to control immune reactivity. The latency of TGFp was shown in human platelets to result from the


Immune Regulation by TGFß

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TGF Has Both Inflammatory and Anti-Inflammatory Properties

Do Tumor Cells Escape Immune Surveillance by Secreting TGF|i? Glioblastomas are among the most malignant tumors for which no curative treatment exists. A cellular immuno­ deficiency state has been observed in patients, character­ ized by cutaneous anergy to a variety of antigens and a de­ crease in T-ccll blastogenic responsiveness in vitro. Tu­

mor-infiltrating lymphocytes harvested after surgery from glioblastoma tissue show no response to T-cell mitogens [52|. Immunosuppressive factors have been described in the tumor cyst fluid of a patient with glioblastoma and in patient serum before but not after tumor removal [for re­ view see Rozman et al., 53], A polypeptide, termed glioblastoma-derived T-ccll suppressor factor (G-TsF), has been identified in the con­ ditioned medium of cultured glioblastoma cells, which in­ hibit the proliferative response of murine T-cell lines to IL-2 and the generation of cytotoxic T cells in allogeneic mixed lymphocyte cultures [16], Purification of G-TsF showed the factor to be a member of the TGFfi family [3, 54, 55], The factor was renamed TGFJI2. By their produc­ tion of immunosuppressive factors namely TGF(I2, glio­ blastoma cells may create an ‘anti-immune network mi­ lieu' which enables the cells to avoid immune recognition and rejection. On the other hand, T cells may escape the effects mediated by TGFfi by losing the receptors for TGFfi. At least in vitro such events do occur. Prolonged cultivation of an MHC class-II-restricted T-helper cell line (OVA-7 T cells) was found to lead to the development of TGFfl-insensitive clones which have lost TGFfi receptors [56]. If such events do occur in vivo, TGFfl-resistant T cells may be able to expand and act despite the presence of ac­ tive TGF[I. The concept of TGF(I to be involved in im­ mune surveillance of tumor cells is supported by the ob­ served rejection of a highly immunogenic murine UV-induced tumor cell line cotransfected with murine TGF|il cDNA and a neomycin-resistance gene [57], Unlike the parent tumor cell lines, the cells producing TGFffl grew progressively in mice without losing the MHC class-I mol­ ecules. However, when these cells were implanted into mice they did not grow progressively in normal recipients; growth was dependent on transient immunosuppression by anti-CD4 antibodies. Thus, a fraction of cytolytic T lym­ phocytes specific for the class-I molecule K216 gene escap­ ed initial suppression by TGFfi and expanded to become sufficient to cause tumor rejection [57]. In conclusion TGFfi produced by glioblastoma may be chemoattractive for mononuclear blood-derived cells, but may also inter­ fere with their immune reactivity towards the tumor. How­ ever, effective immunity against gliomas can also be com­ promised by a lack of tumor antigenicity. At least in mela­ noma effective anti-tumor cytotoxicity has been shown and the tumor antigen characterized recently [58],

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noncovalent association of mature TGFfll to a high molec­ ular weight complex. This complex comprises the latent TGFfl-binding protein which is covalently bound to the homodimerized N-terminal peptide remaining after pro­ teolytic cleavage of the TGFfi precursor [47], Since a ho­ modimer of this N-terminal peptide is sufficient to mask the activity of TGFfi, it was termed latency-associated pep­ tide. Several procedures as transient exposure to extreme pFI, to 8 M urea [47, 48] or to heat [49] are known to acti­ vate L-TGFfI in vitro. However, little is known about the mechanisms leading to activation of L-TGFfi in vivo, e.g. in inflammation. Due to the observations in vitro, it was suggested that L-TGF[I may be activated locally in acidic microenvironments, e.g. in the vicinity of wounded tissues. Whereas there is little data supporting evidence for this hypothesis, other poten­ tial mechanisms have been studied in more detail recently. In cocultures of bovine endothelial cells and either smooth muscle cells or pericytes, activation of L-TGF(I was demonstrated to depend on three factors: (1) contact be­ tween or close apposition of heterotypic cells; (2) binding of L-TGFp to the mannosc-6-phosphate/IGFII receptor on the cell surface, and (3) the activity of proteases like plasmin or urokinase [50]. From these observations the authors concluded that binding of L-TGF(I to mannose-6phosphatc receptors serves to increase the concentration of L-TGFp at the cell surface where proteolytic activation thereby can occur efficiently. Also in glioblastoma cells, proteases were demon­ strated to be essential for the production of active TGF(I2 since several protease inhibitors strongly interfered with the activation but not with the secretion of L-TGF(I2 [51]. In that study, leupeptin which is an inhibitor of lysosomal proteases exhibited the most potent effect. However, it re­ mains elusive whether proteolytic processing of L-TGF|I2 by glioblastoma cells occurs intra- and/or extracellularly. Furthermore, factors such as IFNy, IL-1, TN Fa may regu­ late the balance of proteases and protease inhibitors, and by these properties may be decisive in the activation pro­ cess of TGFfi.

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Immune Regulation by TGF|)

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Modulation of the immune response by transforming growth factor beta.

For the past several years immunologists have been fascinated by a series of experiments showing that transforming growth factor beta (TGF beta) suppr...
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