Jeong Su Do

The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation

Interleukin-1 (IL-1)-mediated signaling in T cells is essential for T helper 17 (Th17) cell differentiation. We showed here that SIGIRR, a negative regulator of IL-1 receptor and Toll-like receptor signaling, was induced during Th17 cell lineage commitment and governed Th17 cell differentiation and expansion through its inhibitory effects on IL-1 signaling. The absence of SIGIRR in T cells resulted in increased Th17 cell polarization in vivo upon myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide immunization. Recombinant IL-1 promoted a marked increase in the proliferation of SIGIRR-deficient T cells under an in vitro Th17 cell-polarization condition. Importantly, we detected increased IL-1-induced phosphorylation of JNK and mTOR kinase in SIGIRR-deficient Th17 cells compared to wild-type Th17 cells. IL-1-induced proliferation was abolished in mTOR-deficient Th17 cells, indicating the essential role of mTOR activation. Our results demonstrate an important mechanism by which SIGIRR controls Th17 cell expansion and effector function through the IL-1-induced mTOR signaling pathway.

T cell-derived IL-3 plays key role in parasite infection-induced basophil production but is dispensable for in vivo basophil survival

Enhanced basophil production is often associated with T(h)2-related conditions such as parasite infections or allergic inflammations. Our previous study demonstrated that T cell activation is necessary to promote basophil production in Nippostrongylus brasiliensis (Nb)-infected mice. Yet, mechanisms underlying how T cells aid infection-induced basophil production are not clear. In this report, we show that IL-3 produced by T cells activated by the infection enhances basophil production in Nb-infected mice. IL-3-deficient mice or Rag2-/- recipients of IL-3-deficient T cells but not of wild-type T cells failed to support basophil production following the Nb infection. Interestingly, although IL-3 was critical for preventing basophil apoptosis in vitro, IL-3 had little contribution to basophil survival and proliferation in vivo. Collectively, these results highlight a novel mechanism by which activation of adaptive immune components induces basophil production but not basophil survival via IL-3 production.

Cutting edge: Spontaneous development of IL-17-producing γδ T cells in the thymus occurs via a TGF-β1-dependent mechanism

In naive animals, γδ T cells are innate sources of IL-17, a potent proinflammatory cytokine mediating bacterial clearance as well as autoimmunity. However, mechanisms underlying the generation of these cells in vivo remain unclear. In this study, we show that TGF-β1 plays a key role in the generation of IL-17+ γδ T cells and that it mainly occurs in the thymus particularly during the postnatal period. Interestingly, IL-17+ γδ TCR+ thymocytes were mainly CD44highCD25low cells, which seem to derive from double-negative 4 γδ TCR+ cells that acquired CD44 and IL-17 expression. Our findings identify a novel developmental pathway during which IL-17–competent γδ T cells arise in the thymus by a TGF-β1–dependent mechanism.

Epithelial Cell-Specific Act1 Adaptor Mediates Interleukin-25-Dependent Helminth Expulsion through Expansion of Lin−c-Kit+ Innate Cell Population

Interleukin-25 (IL-25 or IL-17E), a member of the structurally related IL-17 family, functions as an important mediator of T helper 2 cell-type (type 2) responses. We examined the cell type-specific role of IL-25-induced Act1-mediated signaling in protective immunity against helminth infection. Targeted Act1 deficiency in epithelial cells resulted in a marked delay in worm expulsion and abolished the expansion of the Lin(-)c-Kit(+) innate cell population in the mesenteric lymph node, lung, and liver. Th2 cell-inducing cytokine (IL-25 and IL-33) expression were reduced in the intestinal epithelial cells from the infected and IL-25-injected epithelial-specific Act1-deficient mice. Adoptive transfer of Lin(-)c-Kit(+) cells or combined injection of IL-25 and IL-33 restored the type 2 responses in these mice. Taken together, these results suggest that epithelial-specific Act1 mediates the expansion of the Lin(-)c-Kit(+) innate cell population through the positive-feedback loop of IL-25, initiating the type 2 immunity against helminth infection.

T cell-intrinsic ASC critically promotes TH17-mediated experimental autoimmune encephalomyelitis

Interleukin 1β (IL-1β) is critical for the in vivo survival, expansion and effector function of IL-17–producing helper T (TH17) cells during autoimmune responses, including experimental autoimmune encephalomyelitis (EAE). However, the spatiotemporal role and cellular source of IL-1β during EAE pathogenesis are poorly defined. In the present study, we uncovered a T cell–intrinsic inflammasome that drives IL-1β production during TH17-mediated EAE pathogenesis. Activation of T cell antigen receptors induced expression of pro-IL-1β, whereas ATP stimulation triggered T cell production of IL-1β via ASC-NLRP3–dependent caspase-8 activation. IL-1R was detected on TH17 cells but not on type 1 helper T (TH1) cells, and ATP-treated TH17 cells showed enhanced survival compared with ATP-treated TH1 cells, suggesting autocrine action of TH17-derived IL-1β. Together these data reveal a critical role for IL-1β produced by a TH17 cell–intrinsic ASC–NLRP3–caspase-8 inflammasome during inflammation of the central nervous system.

Cutting Edge: Generation of Colitogenic Th17 CD4 T Cells Is Enhanced by IL-17+ γδ T Cells

Th 17 cells have been implicated in the pathogenesis of colitis; however, a cellular mechanism by which colitogenic Th17 immunity arises in vivo remains unclear. In this study, we report that a subset of IL-17+ γδ T cells plays a crucial role in enhancing in vivo Th17 differentiation and T cell-mediated colitis. TCRβ−/− mice were highly susceptible to T cell-mediated colitis, whereas TCRβδ−/− mice were resistant to the disease. Importantly, cotransfer of IL-17+ but not of IL-17− γδ T cells with CD4 T cells was sufficient to enhance Th17 differentiation and induce full-blown colitis in TCRβδ−/− recipients. Collectively, our results provide a novel function of IL-17+ γδ T cell subsets in supporting in vivo Th17 differentiation and possibly in fostering the development of intestinal inflammation.

IL-15 produced and trans-presented by DCs underlies homeostatic competition between CD8 and γδ T cells in vivo

Homeostatic mechanism by which peripheral T-cell subsets are maintained in vivo remains largely unknown. Using a T-cell proliferation model under lymphopenic settings, we now demonstrate that gammadelta T cells limit CD8 T-cell expansion but not the initial proliferation after transfer into lymphopenic recipients. Interleukin-15 (IL-15) produced by and trans-presented on the membrane of the CD11c(+) dendritic cells (DCs) is the key factor that mediates homeostatic competition between CD8 and gammadelta T cells, revealing previously unrecognized IL-15-dependent homeostatic mechanisms between different T-cell subsets in vivo.

CD4 T cells play important roles in maintaining IL-17-producing γδ T-cell subsets in naive animals.

A proportional balance between αβ and γδ T‐cell subsets in the periphery is exceedingly well maintained by a homeostatic mechanism. However, a cellular mechanism underlying the regulation remains undefined. We recently reported that a subset of developing γδ T cells spontaneously acquires interleukin (IL)‐17‐producing capacity even within naive animals through a transforming growth factor (TGF)β1‐dependent mechanism, thus considered ‘innate’ IL‐17‐producing cells. Here, we report that γδ T cells generated within αβ T cell (or CD4 T cell)‐deficient environments displayed altered cytokine profiles; particularly, ‘innate’ IL‐17 expression was significantly impaired compared with those in wild‐type mice. Impaired IL‐17 production in γδ T cells was directly related to CD4 T‐cell deficiency, because depletion of CD4 T cells in wild‐type mice diminished and adoptive CD4 T‐cell transfer into T‐cell receptor β−/− mice restored IL‐17 expression in γδ T cells. CD4 T cell‐mediated IL‐17 expression required TGFβ1. Moreover, Th17 but not Th1 or Th2 effector CD4 T cells were highly efficient in enhancing γδ T‐cell IL‐17 expression. Taken together, our results highlight a novel CD4 T cell‐dependent mechanism that shapes the generation of IL‐17+ γδ T cells in naive settings.

Differential requirements of MHC and of DCs for endogenous proliferation of different T-cell subsets in vivo

T cells transferred into severe lymphopenic hosts undergo rapid proliferation known as “endogenous proliferation” that are distinct from conventional homeostatic proliferation. Unlike homeostatic proliferation, cytokines, such as IL-7 are dispensable, yet TCR:MHC interaction is essential for this process to occur. However, cell types inducing the proliferation have not formally been addressed. In this study, we report that CD11c+ conventional DCs play irreplaceable roles in inducing endogenous proliferation of both naive and memory phenotype CD4 T cells via TCR-MHC II interaction. By contrast, CD8 T-cell endogenous proliferation was independent of MHC I or CD11c+ DCs. Interestingly, MHC II was necessary to support naive CD8 T-cell proliferation within MHC I-deficient hosts. Depletion of both B cells and DCs was sufficient to abrogate the proliferation of naive but not of memory CD8 T cells. These results suggest that depending on the T-cell lineages, as well as the differentiation status, different mechanisms control endogenous proliferation, revealing in vivo complexity of T-cell proliferation under lymphopenic conditions.

Colitogenic effector T cells: roles of gut homing integrin, gut antigen specificity, and γδ T cells

Disturbance of T‐cell homeostasis could lead to intestinal inflammation. Naive CD4 T cells undergoing spontaneous proliferation, a robust proliferative response that occurs under severe lymphopenic conditions, differentiate into effector cells producing Th1‐ and/or Th17‐type cytokines and induce a chronic inflammation in the intestine that resembles human inflammatory bowel disease. In this study, we investigated the key properties of CD4 T cells necessary to induce experimental colitis. α4β7 upregulation was primarily induced by mesenteric lymph node (mLN) resident CD11b+ dendritic cell subsets via transforming growth factor beta (TGFβ)/retinoic acid‐dependent mechanism. Interestingly, α4β7 expression was essential but not sufficient to induce inflammation. In addition to gut‐homing specificity, expression of gut Ag specificity was also crucial. T‐cell acquisition of the specificity was dramatically enhanced by the presence of γδ T cells, a population previously shown to exacerbate T‐cell‐mediated colitis. Importantly, interleukin (IL)‐23‐mediated γδ T cell stimulation was necessary to enhance colitogenicity but not gut antigen reactivity of proliferating CD4 T cells. These findings demonstrate that T‐cell colitogenicity is achieved through multiple processes, offering a therapeutic rationale by intervening these pathways.