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Myd88 Is Essential to Sustain Mtor Activation Necessary to Promote T Helper 17 Cell Proliferation by Linking IL-1 and IL-23 Signaling

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Myd88 Is Essential to Sustain Mtor Activation Necessary to Promote T Helper 17 Cell Proliferation by Linking IL-1 and IL-23 Signaling MyD88 is essential to sustain mTOR activation necessary to promote T helper 17 cell proliferation by linking IL-1 and IL-23 signaling JiHoon Changa,1, Patrick R. Burkettb,c, Christopher M. Borgesd, Vijay K. Kuchroob, Laurence A. Turkae,2, and Cheong-Hee Changa,2 aDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; bCenter for Neurologic Diseases and cPulmonary and Critical Care Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; dThe Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and eDepartment of Surgery, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129 Edited by Richard A. Flavell, Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT, and approved December 19, 2012 (received for review April 10, 2012) Myeloid differentiation primary response protein 88 (MyD88) is proinflammatory cytokines was shown to be critical in the sup- classically known as an adaptor, linking TLR and IL-1R to down- port of Th17 cell differentiation (8, 11, 12). In particular, an stream signaling pathways in the innate immune system. In inflammatory cytokine, IL-6, favors Th17 cell development by addition to its role in innate immune cells, MyD88 has been shown inhibiting regulatory T cells (13). The role of IL-1 in Th17 cell to play an important role in T cells. How MyD88 regulates helper differentiation has been investigated as well. IL-1 receptor type − − T-cell differentiation remains largely unknown, however. Here 1-deficient (Il1r1 / ) mice showed a lower incidence of EAE and we demonstrate that MyD88 is an important regulator of IL-17- severe defects in the induction of IL-17–producing T cells (14). + producing CD4 T helper cells (Th17) cell proliferation. MyD88-de- IL-1 signaling in T cells was further shown to be involved in early + ficient CD4 T cells showed a defect in Th17 cell differentiation, Th17 cell differentiation by regulating IFN regulatory factor 4 but not in Th1 cell or Th2 cell differentiation. The impaired IL-17 γ γ + and RAR-related orphan receptor t (ROR t) (15). production from MyD88-deficient CD4 T cells is not a result of Although roles for MyD88 in the innate immune system are defective RAR-related orphan receptor γt (RORγt) expression. In- well established, little is known about their potential function in stead, MyD88 is essential for sustaining the mammalian target of the adaptive immune system. Several studies have demonstrated rapamycin (mTOR) activation necessary to promote Th17 cell pro- + important roles of MyD88 in T cells. For instance, T-cell ex- liferation by linking IL-1 and IL-23 signaling. MyD88-deficient CD4 pression of MyD88 is required for resistance to Toxoplasma + T cells showed impaired mTOR activation and, consequently, re- gondii (16); the MyD88-dependent signaling pathway in CD4 duced Th17 cell proliferation. Importantly, the absence of MyD88 T cells has been shown to enhance proliferation and augment in T cells ameliorated disease in the experimental autoimmune en- humoral immune responses (17); and MyD88 is required for T- cephalomyelitis model. Taken together, our results demonstrate cell effector function in the development of inflammatory bowel − − that MyD88 has a dual function in Th17 cells by delivering IL-1 disease (18). Interestingly, although Myd88 / T cells were found signaling during the early differentiation stage and integrating IL- to exhibit decreased IL-17 production (18), how T-cell differen- 23 signaling to the mTOR complex to expand committed Th17 cells. tiation could be regulated by MyD88 was not clear in that study. Here we investigated the molecular mechanism by which + yeloid differentiation primary response protein 88 (MyD88) MyD88 regulates CD4 T-cell differentiation. Our results dem- Mwas originally isolated as a cloned cDNA that was induced in onstrate that MyD88 contributes to Th17 cell differentiation, but M1 myeloblastic leukemia cells on activation with IL-6 (1). The not to Th1 or Th2 cell differentiation. Both IL-1 and IL-23 sig- function of MyD88 was then uncovered, because the C-terminal naling depend on MyD88 and result in up-regulation of IL-23R. portion of MyD88 was found to be similar to the Drosophila Toll MyD88-deficient Th17 cells show reduced IL-23R expression and receptor and the mammalian IL-1 receptor (IL-1R) (2). This mTOR activation, leading to impaired Th17 cell proliferation. conserved region in the cytoplasmic tails of IL-1R and Toll-like Furthermore, MyD88 is crucial for proper Th17 cell differentia- receptor (TLR) is referred to as the Toll/IL-1R (TIR) domain. tion in vivo. Thus, our findings reveal a unique role for the innate MyD88 is now known to play an essential role in the innate im- adaptor MyD88 in the regulation of Th17 cell differentiation. mune response by linking members of the TLR and IL-1R su- perfamily to the downstream activation of NF-κB and MAPKs (3). Results Among cytokines produced by activated innate immune cells, IL- Impaired IL-17A Production in MyD88-Deficient CD4+ T Cells. MyD88- − − 23 has been shown to promote production of the proinflammatory deficient (Myd88 / ) T cells have been shown to exhibit de- + cytokine IL-17 in activated T cells (4). IL-17–producing CD4 creased IL-17 production (18), but the underlying mechanism T helper (Th17) cells were identified after the discovery that IL- 23 is linked to traditionally Th1-associated autoimmune dis- orders, such as experimental autoimmune encephalitis (EAE). Author contributions: J.C., P.R.B., and C.-H.C. designed research; J.C., P.R.B., and C.M.B. − − − − Il23a / mice, but not Il12a / mice, were shown to be autoim- performed research; V.K.K. and L.A.T. contributed new reagents/analytic tools; J.C., P.R.B., V.K.K., L.A.T., and C.-H.C. analyzed data; and J.C., P.R.B., L.A.T., and C.-H.C. wrote mune-resistant (5). IL-23 is required for Th17 cell-mediated the paper. autoimmune disorders in vivo, but the role of IL-23 in Th17 cell The authors declare no conflict of interest. differentiation remains controversial (6). Previous studies sup- This article is a PNAS Direct Submission. port the idea that IL-23 helps expand or maintain Th17 cells (7– 1Present address: The Transplant Institute, Beth Israel Deaconess Medical Center, Harvard 9). In addition, a recent study reemphasized the importance of Medical School, Boston, MA 02215. IL-23 in the generation of pathogenic Th17 cells, showing that 2To whom correspondence may be addressed. E-mail: [email protected] or heechang@ they can be generated with IL-23, IL-6, and IL-1β (10). umich.edu. β In addition to IL-23, other cytokines, including TGF- , IL-6, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. and IL-1, play roles in Th17 cell development. TGF-β with 1073/pnas.1206048110/-/DCSupplemental. 2270–2275 | PNAS | February 5, 2013 | vol. 110 | no. 6 www.pnas.org/cgi/doi/10.1073/pnas.1206048110 Downloaded by guest on September 27, 2021 AB under Th1 cell-polarizing conditions or IL-4 production under Th2 cell-polarizing conditions (Fig. 1A). Given our observation of impaired IL-17A production after T-cell restimulation, we next asked whether the defect started − − + during T-cell differentiation. Myd88 / CD4 T cells already + showed a lower frequency of IL-17A cells after 3 d of Th17 cell differentiation (Fig. S1A), although the defect was less dramatic − − + than that observed after restimulation. Again, Myd88 / CD4 T cells showed no defect in IFN-γ expression under Th1 cell-po- larizing conditions (Fig. S1A). In addition, the induction of Il17a − − + mRNA was poorer in Myd88 / CD4 T cells compared with WT under Th17 cell-polarizing conditions; however, Ifng mRNA levels − − + were comparable in WT and Myd88 / CD4 T cells (Fig. S1B). Along with IL-17A, the production of IL-17F, another IL-17 cy- − − + tokine family member, was severely impaired from Myd88 / CD4 T cells after restimulation, and the defect in Il17f mRNA level was C detected based on the early Th17 cell differentiation (Fig. S1C). RORγt Is Expressed Normally in Myd88−/− Th17 Cells. IL-2 or IL-10 signaling has been shown to modulate Th17 cell generation (19, 20); however, in the present study, impaired IL-17 production in − − + Myd88 / CD4 T cells was not related to increased IL-2 or − − + IL-10 production (Fig. S2). Given that Myd88 / CD4 T cells are defective in IL-17 production under Th17 cell-polarizing conditions but not in IFN-γ or IL-4 production under Th1 or Th2 + Fig. 1. Impaired production of IL-17A in MyD88-deficient CD4 Tcellsis cell-polarizing conditions, respectively, we speculated that the − − + independent of RORγt. (A)Purified Myd88 / or WT CD4 T cells were defect might result from cytokine signaling specific to Th17 cell cultured under Th1-, Th2-, or Th17-polarizing conditions for 5 d, followed differentiation. Among Th17-skewing cytokines, including TGF- by restimulation with plate-bound anti-CD3 for 24 h, as described in β, IL-6, IL-1β, and IL-23, we first focused on IL-1β because of the Materials and Methods. ELISA was performed to detect the amounts of + well-established role of MyD88 as an adaptor in IL-1R signaling IFN-γ, IL-4, and IL-17A in culture supernatants. *P < 0.05. (B)Purified CD4 − − (3). Indeed, the defect in IL-17A production from Myd88 / cells were cultured in the presence of the indicated cytokines for 3 d, and + β Foxp3 and IL-17A expression was analyzed by flow cytometry.
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