Theme 2: Immune tolerance and T-cell function
Overview: CD4+ helper T cells mediate cellular immunity and tissue inflammation as well as help the activation of B cells and CD8+ T cells. CD8+ cytotoxic T cells (CTLs) function as important anti-tumor effector cells in addition to mediating anti-viral immunity. Immunosuppressive regulatory T (Treg) cells function to maintain normal immune homeostasis and prevent autoimmunity; however, this population of T cells also hampers anti-tumor immunity. Thus, several CCIR members continue to study the development, function and homeostasis of different T cell subsets in order to find ways to manipulate the adaptive immune system for improving the efficacy of cancer immunotherapy.
Some highlights from the past year include:
• 4-1BB agonist antibody treatment induces a population of KLRG1+ T cells that infiltrate melanoma tumors and investigation of the origin and function of these cells, as well as their place within established T cell paradigms revealed that these T cells, particularly the CD4 lineage, represent a novel phenotype characterized by enhanced, multipotent cytotoxicity; this novel phenotype resolves multiple questions associated with 4-1BB activation, including how 4-1BB enhances tumor-specific cytotoxicity and how 4-1BB can promote tumor immunity while repressing autoimmunity (Curran MA, J Exp Med. 2013)
Additional Relevant Publications:
- Liu X, Yan X, Zhong B, Nurieva RI, Wang A, Wang X, Martin-Orozco N, Wang Y, Chang SH, Esplugues E, Flavell RA, Tian Q, Dong C. Bcl6 expression specifies the T follicular helper cell program in vivo. J Exp Med. 2012, 209(10):1841-52.
- Reynolds JM, Martinez GJ, Chung Y, Dong C. Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation. Proc Natl Acad Sci U S A. 2012, 109(32):13064-9.
- Chang JH, Xiao Y, Hu H, Jin J, Yu J, Zhou X, Wu X, Johnson HM, Akira S, Pasparakis M, Cheng X, Sun SC. Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. Nat Immunol. 2012, 13(5):481-90.
- Nurieva RI, Podd A, Chen Y, Alekseev AM, Yu M, Qi X, Huang H, Wen R, Wang J, Li HS, Watowich SS, Qi H, Dong C, Wang D. STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J Biol Chem. 2012, 287(14):11234-9.
- Wang X, Zhang Y, Yang XO, Nurieva RI, Chang SH, Ojeda SS, Kang HS, Schluns KS, Gui J, Jetten AM, Dong C. Transcription of Il17 and Il17f is controlled by conserved noncoding sequence 2. Immunity. 2012, 36(1):23-31.
- Chang M, Jin W, Chang JH, Xiao Y, Brittain GC, Yu J, Zhou X, Wang YH, Cheng X, Li P, Rabinovich BA, Hwu P, Sun SC. The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity. Nat Immunol. 2011, 12(10):1002-9.
- Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, Wang YH, Lim H, Reynolds JM, Zhou XH, Fan HM, Liu ZM, Neelapu SS, Dong C. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011, 17(8):983-8.
- Hu H, Wu X, Jin W, Chang M, Cheng X, Sun SC. Noncanonical NF-kappaB regulates inducible costimulator (ICOS) ligand expression and T follicular helper cell development. Proc Natl Acad Sci U S A. 2011, 108(31):12827-32.
- Yamazaki T, Goya I, Graf D, Craig S, Martin-Orozco N, Dong C. A butyrophilin family member critically inhibits T cell activation. J Immunol. 2010, 185(10):5907-14.
- Carreño R, Brown WS, Li D, Hernandez JA, Wang Y, Kim TK, Craft JW Jr, Komanduri KV, Radvanyi LG, Hwu P, Molldrem JJ, Legge GB, McIntyre BW, Ma Q. 2E8 binds to the high affinity I-domain in a metal ion-dependent manner: a second generation monoclonal antibody selectively targeting activated LFA-1. J Biol Chem. 2010, 285(43):32860-8.
- Martinez GJ, Zhang Z, Reynolds JM, Tanaka S, Chung Y, Liu T, Robertson E, Lin X, Feng XH, Dong C. Smad2 positively regulates the generation of Th17 cells. J Biol Chem. 2010, 285(38):29039-43.
- Nurieva RI, Zheng S, Jin W, Chung Y, Zhang Y, Martinez GJ, Reynolds JM, Wang SL, Lin X, Sun SC, Lozano G, Dong C. The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation. Immunity. 2010, 32(5):670-80.
- Reynolds JM, Pappu BP, Peng J, Martinez GJ, Zhang Y, Chung Y, Ma L, Yang XO, Nurieva RI, Tian Q, Dong C. Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity. 2010, 32(5):692-702.
- Lee AJ, Wu X, Cheng H, Zhou X, Cheng X, Sun SC. CARMA1 regulation of regulatory T cell development involves modulation of interleukin-2 receptor signaling. J Biol Chem. 2010, 285(21):15696-703.
- Angkasekwinai P, Chang SH, Thapa M, Watarai H, Dong C. Regulation of IL-9 expression by IL-25 signaling. Nat Immunol. 2010, 11(3):250-6.
- Martinez GJ, Zhang Z, Chung Y, Reynolds JM, Lin X, Jetten AM, Feng XH, Dong C. Smad3 differentially regulates the induction of regulatory and inflammatory T cell differentiation. J Biol Chem. 2009, 284(51):35283-6.
- Yang XO, Angkasekwinai P, Zhu J, Peng J, Liu Z, Nurieva R, Liu X, Chung Y, Chang SH, Sun B, Dong C. Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment. Nat Immunol. 2009, 10(12):1260-6.
- Zhang Y, Reynolds JM, Chang SH, Martin-Orozco N, Chung Y, Nurieva RI, Dong C. MKP-1 is necessary for T cell activation and function. J Biol Chem. 2009, 284(45):30815-24.
- Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, Wang YH, Dong C. Bcl6 mediates the development of T follicular helper cells. Science. 2009, 325(5943):1001-5.
- Li D, Molldrem JJ, Ma Q. LFA-1 regulates CD8+ T cell activation via T cell receptor-mediated and LFA-1-mediated Erk1/2 signal pathways. J Biol Chem. 2009, 284(31):21001-10.
- Jin W, Zhou XF, Yu J, Cheng X, Sun SC. Regulation of Th17 cell differentiation and EAE induction by MAP3K NIK. Blood. 2009, 113(26):6603-10.
- Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS, Ma L, Watowich SS, Jetten AM, Tian Q, Dong C. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity. 2009, 30(4):576-87.
- Liu X, Alexiou M, Martin-Orozco N, Chung Y, Nurieva RI, Ma L, Tian Q, Kollias G, Lu S, Graf D, Dong C. Cutting edge: A critical role of B and T lymphocyte attenuator in peripheral T cell tolerance induction. J Immunol. 2009, 182(8):4516-20.
- Wang Y, Li D, Nurieva R, Yang J, Sen M, Carreño R, Lu S, McIntyre BW, Molldrem JJ, Legge GB, Ma Q. LFA-1 affinity regulation is necessary for the activation and proliferation of naive T cells. J Biol Chem. 2009, 284(19):12645-53.
- Chang M, Lee AJ, Fitzpatrick L, Zhang M, Sun SC. NF-kappa B1 p105 regulates T cell homeostasis and prevents chronic inflammation. J Immunol. 2009, 182(5):3131-8.
- Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, Wang YH, Watowich SS, Jetten AM, Tian Q, Dong C. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008, 29(1):138-49.
- Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, Shah B, Chang SH, Schluns KS, Watowich SS, Feng XH, Jetten AM, Dong C. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity. 2008, 29(1):44-56.
- Pappu BP, Borodovsky A, Zheng TS, Yang X, Wu P, Dong X, Weng S, Browning B, Scott ML, Ma L, Su L, Tian Q, Schneider P, Flavell RA, Dong C, Burkly LC. TL1A-DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease. J Exp Med. 2008, 205(5):1049-62.
- Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008, 28(1):29-39.