CRACR2A-Mediated TCR Signaling Promotes Local Effector Th1 and Th17 Responses

被引:18
作者
Woo, Jin Seok [1 ]
Srikanth, Sonal [1 ]
Kim, Kyun-Do [1 ]
Elsaesser, Heidi [2 ,3 ]
Lu, Jing [4 ]
Pellegrini, Matteo [4 ]
Brooks, David G. [2 ,3 ]
Sun, Zuoming [5 ]
Gwack, Yousang [1 ]
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Ctr Hlth Sci 53 266, 10833 Le Conte Ave, Los Angeles, CA 90095 USA
[2] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada
[3] Univ Toronto, Dept Immunol, Toronto, ON M5G 2M9, Canada
[4] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA
[5] City Hope Natl Med Ctr, Beckman Res Inst, Div Mol Immunol, Duarte, CA 91010 USA
基金
美国国家卫生研究院;
关键词
CYTOKINE GM-CSF; T-CELLS; CUTTING EDGE; TRANSCRIPTION; EXPRESSION; RECEPTOR; PROTEIN; BET; DIFFERENTIATION; DYSREGULATION;
D O I
10.4049/jimmunol.1800659
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Ca(2+)release-activated Ca2+ channel regulator 2A (CRACR2A) is expressed abundantly in T cells and acts as a signal transmitter between TCR stimulation and activation of the Ca2+/NFAT and JNK/AP1 pathways. CRACR2A has been linked to human diseases in numerous genome-wide association studies and was shown to be one of the most sensitive targets of the widely used statin drugs. However, the physiological role of CRACR2A in T cell functions remains unknown. In this study, using transgenic mice for tissue-specific deletion, we show that CRACR2A promotes Th1 responses and effector function of Th17 cells. CRACR2A was abundantly expressed in Th1 and Th17 cells. In vitro, deficiency of CRACR2A decreased Th1 differentiation under nonpolarizing conditions, whereas the presence of polarizing cytokines compensated this defect. Transcript analysis showed that weakened TCR signaling by deficiency of CRACR2A failed to promote Th1 transcriptional program. In vivo, conditional deletion of CRACR2A in T cells alleviated Th1 responses to acute lymphocytic choriomeningitis virus infection and imparted resistance to experimental autoimmune encephalomyelitis. Analysis of CNS from experimental autoimmune encephalomyelitis-induced mice showed impaired effector functions of both Th1 and Th17 cell types, which correlated with decreased pathogenicity. Collectively, our findings demonstrate the requirement of CRACR2A-mediated TCR signaling in Th1 responses as well as pathogenic conversion of Th17 cells, which occurs at the site of inflammation.
引用
收藏
页码:1174 / 1185
页数:12
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