Editors' ChoiceImmunology

Giving T cells the NOD

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Sci. Signal.  05 May 2015:
Vol. 8, Issue 375, pp. ec117
DOI: 10.1126/scisignal.aac4773

Nucleotide-binding oligomerization domain (NOD)–like receptors (NLRs) are intracellular pattern recognition receptors. Stimulation of NLRs activates nuclear factor κB (NF-κB) signaling in innate immune cells, such as macrophages, resulting in inflammatory cytokine production. Noting that mutations in the gene encoding NLRP12 are associated with autoinflammatory disorders, Lukens et al. investigated a role for this NLR in T cells. NLRP12-deficient (Nlrp12–/–) mice immunized with MOG peptide—which induces experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis—had a greater proportion of CD4+ T cells that produced proinflammatory cytokines after stimulation in vitro than did MOG-immunized wild-type mice. However, unlike the wild-type mice that exhibited paralysis as a result of MOG-induced EAE, the Nlrp12–/– mice developed atypical EAE disease, exhibiting ataxia and loss of balance rather than paralysis. These symptoms were associated with increased numbers of interleukin-4 (IL-4)–producing CD4+ T cells in the central nervous system and spleens of the Nlrp12–/– mice compared with the wild-type mice. Indeed, treatment of MOG-immunized Nlrp12–/– mice with an IL-4–neutralizing antibody resulted in paralysis, consistent with a reversion to the classical form of EAE disease observed in the MOG-immunized wild-type mice. In a mouse model of colitis, mice that received Nlrp12–/– CD4+ T cells exhibited increased inflammation and disease severity compared with mice that received wild-type CD4+ T cells. The Nlrp12–/– CD4+ T cells isolated from these mice also produced more proinflammatory cytokines after stimulation in vitro than did the isolated wild-type CD4+ T cells. Furthermore, the isolated Nlrp12–/– CD4+ T cells had increased activation of both canonical and noncanonical NF-κB signaling compared with isolated wild-type CD4+ T cells. Together, these data suggest a mechanism by which NLRP12 inhibits NF-κB signaling in T cells to reduce cytokine production and decrease the severity of T cell–mediated disorders. As Thaiss and Elinav discuss in a commentary, these findings highlight the cell type–specificity of NLR responses and increase our understanding of the mechanisms that underlie T cell–dependent autoinflammatory disorders.

J. R. Lukens, P. Gurung, P. J. Shaw, M. J. Barr, Md. H. Zaki, S. A. Brown, P. Vogel, H. Chi, T.-D. Kanneganti, The NLRP12 sensor negatively regulates autoinflammatory disease by modulating interleukin-4 production in T cells. Immunity 42, 654–664 (2015).[PubMed]

C. A. Thaiss, E. Elinav, NF-κB regulation by NLRs: T cells join the club. Immunity 42, 595–597 (2015). [PubMed]