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ne w s and v ie w s stimulation of the cells with the phorbol ester PMA and ionomycin, which bypass the TCR signaling and therefore bypass any immediate effects of TCR affinity or ‘coagonism’. These results indicate that the functional differences between CD5hi LLO56 and CD5lo LLO118 cells are ‘prewired’ into the cells (Fig. 1c). Ostensibly, that ‘prewiring’ is set by the avidity of T cells for ‘self ’ during the development of those T cells, as the same phenotype is observed for mature thymocytes but not immature thymocytes. Moreover, continued engagement of self peptide–MHC is needed to maintain this ‘wiring’, as much of the phenotype of the T cells is lost when these cells are first deprived of contact with self peptide–MHC. The findings by Persaud et al. challenge the notion that all naive T cells exist as a ‘blank slate’, each waiting to receive instructions for differentiation upon encountering their cognate foreign antigen4. Instead, the divergent activation programs of LLO56 and LLO118 cells are ‘encoded’ during their development and are maintained in the periphery by the distinct avidities of their TCRs for self molecules4. Although the present findings do not refute ‘coagonism’, they clearly indicate that avidity for self can ‘program’ the response of the T cell before its encounter with foreign antigen, presumably without affecting its affinity for the foreign antigen. The situation seems to be even more complex, as the relative effect and dependence on self peptide– MHC ligands to maintain activation programs vary according to the strength of the avidity for self molecules. Here, the authors do an in vivo experiment wherein self peptide–MHC ligands are withheld before exposure to infection with L. monocytogenes but are made available during that infection (i.e., ‘coagonism’ is unchanged but ‘pre-coagonism’ is decreased).

Persaud et al. find that although deprivation of contact with self peptide–MHC before activation negatively affects the response of each clone, the population expansion of LLO118 cells is largely unaffected, while that of LLO56 cells is diminished even further4. Thus, the relatively higher avidity of LLO56 cells for self molecules correlates with a stronger activation response in terms of the phosphorylation of Erk and production of IL-2, as well as a greater dependence on contact with self peptide–MHC ligands for the clone to mount any response at all. Collectively, the present findings do not easily fit into either of the two proposals discussed above on how avidity for self molecules influences the response of a T cell to its cognate foreign antigen. Alone, each model is probably too simplistic, and the present work demands that another stage—‘imprinting’ and ‘tuning’ during the development and maintenance of T cells—must be considered. It is also possible that clonal variations exist in the relative roles of avidity for self molecules at each of these stages. The concern that some of the present findings could be an artifact of the transgenic system is probably not applicable, as other ‘founders’ of the two lines display the same phenotype8. Nonetheless, despite the authors’ observation of a similar trend in sorted CD5hi and CD5lo polyclonal T cell subsets, these data are much less convincing than are those obtained with LLO56 and LLO118 cells. Further work is warranted before the relative applicability of the current proposal, as well as that of the two other competing (or perhaps parallel) ideas, to T cells under normal physiological conditions can be determined. In closing, the picture that emerges from the data presented by Persaud et al. is one in which

the foreign antigen–driven IL-2 response of a T cell is preordained by the avidity of its TCR for self peptide–MHC; higher avidity for self molecules correlates with more robust immediate IL-2 production4. What role is served by the enhanced IL-2 response? It is conceivable that the CD5hi T cells participate in the initiation of the immune response by producing copious IL-2 and, having filled that role, die. Alternatively, instead of being their raison d’être, the enhanced IL-2 production of CD5hi T cells may simply represent an autocrine aspect of their preassigned ‘suicide program’. Curiously, not all LLO56 cells die during primary infection, and the population expansion of LLO56 cells actually outstrips that of LLO118 cells in the secondary response8. What causes this reversal of fates? In addition to defining the prevalence of naive T cells with the peculiar activation program of LLO56, future research should delve into the importance of these characteristics in terms of host health. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Sprent, J. & Surh, C.D. Nat. Immunol. 12, 478–484 (2011). 2. Krogsgaard, M., Juang, J. & Davis, M.M. Semin. Immunol. 19, 236–244 (2007). 3. Gascoigne, N.R., Zal, T., Yachi, P.P. & Hoerter, J.A. Curr. Top. Microbiol. Immunol. 340, 171–189 (2010). 4. Persaud, S.P., Parker, C.R., Lo, W.-L., Weber, K.S. & Allen, P.M. Nat. Immunol. 15, 266–274 (2014). 5. Krogsgaard, M. et al. Nature 434, 238–243 (2005). 6. Yachi, P.P., Ampudia, J., Gascoigne, N.R. & Zal, T. Nat. Immunol. 6, 785–792 (2005). 7. Mandl, J.N., Monteiro, J.P., Vrisekoop, N. & Germain, R.N. Immunity 38, 263–274 (2013). 8. Weber, K.S. et al. Proc. Natl. Acad. Sci. USA 109, 9511–9516 (2012). 9. Azzam, H.S. et al. J. Exp. Med. 188, 2301–2311 (1998).

Inducible nitric oxide synthase is crucial for plasma cell survival Modesta N Njau & Joshy Jacob The viability of long-lived plasma cells is enhanced by the expression of inducible nitric oxide synthase, which relieves endoplasmic reticulum stress by triggering a response dependent on cGMP and protein kinase G.

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lasma cells, which are terminally differentiated B cells, are the workhorses of humoral immunity. There are two types of

Modesta N. Njau and Joshy Jacob are with the Emory Vaccine Center, Department of Microbiology & Immunology and Yerkes National Primate Center, Emory University, Atlanta, Georgia, USA. e-mail: : [email protected]

these cells: short-lived plasma cells and longlived plasma cells1. Short-lived plasma cells are generated within a few days after infection and die after 2 weeks. The antibodies secreted by short-lived plasma cells help to control the infection. Meanwhile, long-lived plasma cells, which are generated through the germinal-center pathway, migrate and take up residence in the bone marrow and

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continue to secrete copious amounts of antibodies, usually throughout the host’s lifespan. Long-lived plasma cells confer longterm protection to the host and hence their longevity is pivotal in their ability to provide long-lasting immunological protection. Long-lived plasma cells reside in the bone marrow, where stromal cells, eosinophils and basophils provide survival factors, 219

ne w s and v ie w s IL-6

APRIL BCMA

IL-6R

TACI

PC differentiation & UPR Jak XBP-1 iNOS STAT

MAPK

NF-κB NO

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Survival

Survival

Figure 1 A working model for iNOS-mediated enhancement of plasma cell survival. During the terminal differentiation of plasma cells and the UPR, XBP-1 is cleaved, and it induces iNOS expression. Then, iNOS catalyzes NO production, which in turn promotes the survival of plasma cells by serving as an intermediate in signaling via APRIL and IL-6. At present it is unknown where NO intersects with the signaling cascades of APRIL and IL-6. IL-6R, receptor for IL-6; BCMA, B cell–maturation antigen; TACI, transmembrane activator; PC, plasma cell; Jak, kinase; STAT, transcription factor; MAPK, mitogen-activated protein kinase; NF-κB, transcription factor.

such as interleukin 6 (IL-6), the chemokine CXCL12 and the proliferation-inducing ligand APRIL, that facilitate their survival1. In this issue of Nature Immunology, Anna George and colleagues demonstrate that inducible nitric oxide synthase (iNOS) is an intermediate in signaling pathways that promote the survival of plasma cells2. They show that deficiency in iNOS results in a shorter lifespan for plasma cells, while it has no effect on the activation and terminal differentiation of B cells. Through studies of iNOS-deficient plasma cells and iNOS inhibitors, they demonstrate that iNOS is involved in signaling via IL-6 and APRIL, both of which are critical for the survival of plasma cells in the bone marrow3,4. Furthermore, they show that iNOS probably promotes the survival of plasma cells through a pathway of iNOS, nitric oxide (NO), cGMP and protein kinase G (Fig. 1). NO is the smallest known signaling messenger; it has numerous pivotal functions in mammalian physiology. It is produced by three isoforms of nitric oxide synthases: endothelial nitric oxide synthase, neuronal nitric oxide synthase and iNOS5. All these are homodimers that catalyze the production of nitric oxide from l-arginine. While the endothelial and neuronal nitric oxide synthases are constitutively expressed and initiate a wide range of cellular processes, including myocardial function and neurotransmission, 220

iNOS is transcriptionally regulated and is induced by cytokines, lipopolysaccharide and other microbial agents 5. As indicated by its mode of activation, iNOS serves as a signaling mediator during host responses to infection and it is also associated with septic shock. The role of iNOS in macrophages has been extensively studied; when induced, macrophages produce a large amount of NO, which facilitates the elimination of microbes5. Published studies have shown that iNOS can be induced in other cells of the immune system and those not of the immune system and can mediate the elimination of microbes, parasites and tumor cells5. Interestingly, iNOS is also associated with both cell death6,7 and cell survival8,9. Prior to this insightful study by George and colleagues2, there was no direct link between iNOS and the survival of plasma cells. However, a published study demonstrating that iNOS modulates endoplasmic reticulum (ER) stress10 hinted a possible role of iNOS in the function of plasma cells. The ER stress response occurs when excess proteins accumulate in the ER. This response occurs in plasma cells, since they continuously synthesize large quantities of antibodies. To cope with that intense protein production, plasma cells induce the unfolded protein response (UPR), which increases the efficiency of protein processing and prevents the apoptosis that would otherwise ensue

with unrestrained ER stress. There are three main molecular branches of the UPR: the serine-threonine kinase and transmembrane endonuclease IRE-1, the ER stress–resistant kinase PERK, and the transcription activator ATF-6. Activation of those molecules results in the production of the transcription factors XBP-1, ATF-4 and ATF-6(N), respectively; these activate genes encoding molecules that facilitate protein processing in the ER11. The activation of PERK and IRE-1 leads to the induction of genes encoding molecules that promote mRNA decay, to decrease the protein-folding load of the ER. In contrast, ATF-6 activates genes encoding molecules that increase proteinfolding capacity of the ER. XBP-1 is a transcription factor and signaling molecule that is activated by and signals downstream of IRE-1 and ATF-6 in the UPR. It exists in two forms: unspliced and spliced. ER stress activates IRE-1, which processes XBP-1 mRNA to generate the spliced version of the protein, which activates genes encoding enzymes that degrade misfolded proteins. Spliced XBP-1 also promotes expression of the gene encoding NOS; interestingly, the ensuing increase in NO also modulates ER stress by resulting in the upregulation of genes encoding ER-resident chaperones12. Consistent with those reports, the present study by George and colleagues suggests that iNOS expression in plasma cells promotes protein processing during the ER stress response2. In the absence of iNOS, they detect a lower abundance of mRNA encoding XBP-1, Gadd34, EDEM1 and GRP94, all of which are involved in alleviating ER stress. However, it is yet to be determined whether NO has an effect on the abundance of spliced XBP-1, which mediates ER stress relief. The results of published reports10 and the present study2 would indicate that iNOS and XBP-1 might regulate each other; however, further studies are needed to confirm this hypothesis. George and colleagues have brought awareness of the involvement of iNOS and NO in the lifespan of plasma cells 2; this contribution will have tangible effects on the future of research into plasma cells. For example, it may be worth exploring whether iNOS-NO can be used in attempts to enhance the longevity of plasma cells, especially in a vaccine setting. The physiological and potential pathological roles of iNOS and NO in plasma cells should also be scrutinized, given that in macrophages, the role of iNOS-NO has been studied extensively, and it is known that the NO induced is sometimes toxic to healthy cells,

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ne w s and v ie w s COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Tangye, S.G. Trends Immunol. 32, 595–602 (2011). 2. Saini, A.S., Shenoy, G.N., Rath, S., Bal, V. & George, A. Nat. Immunol. 15, 275–282 (2014). 3. Minges Wols, H.A., Underhill, G.H., Kansas, G.S. & Witte, P.L. J. Immunol. 169, 4213–4221 (2002). 4. O’Connor, B.P. et al. J. Exp. Med. 199, 91–98 (2004). 5. Forstermann, U. & Sessa, W.C. Eur. Heart J. 33, 829–837, 837a-837d (2012).

6. Salgo, M.G., Squadrito, G.L. & Pryor, W.A. Biochem. Biophys. Res. Commun. 215, 1111–1118 (1995). 7. Loweth, A.C., Williams, G.T., Scarpello, J.H. & Morgan, N.G. FEBS Lett. 400, 285–288 (1997). 8. Genaro, A.M., Hortelano, S., Alvarez, A., Martinez, C. & Bosca, L. J. Clin. Invest. 95, 1884–1890 (1995). 9. Liu, L. & Stamler, J.S. Cell Death Differ. 6, 937–942 (1999). 10. Guo, F., Lin, E.A., Liu, P., Lin, J. & Liu, C. Cell. Signal. 22, 1818–1828 (2010). 11. Walter, P. & Ron, D. Science 334, 1081–1086 (2011). 12. Xu, W., Liu, L., Charles, I.G. & Moncada, S. Nat. Cell Biol. 6, 1129–1134 (2004).

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which leads to tissue damage and possibly nonspecific allograft rejection. Finally, it would be of great interest to determine whether iNOS and NO operate in myelomas and if their down-modulation could be used as a therapeutic tool in the fight against plasma cell neoplasias. Likewise, the role of iNOS-NO could also be explored in the context of modulating plasma cells in autoimmunity.

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Inducible nitric oxide synthase is crucial for plasma cell survival.

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