Stromal Interaction Molecule Deficiency in T Cells Promotes Spontaneous Follicular Helper T Cell Development and Causes Type 2 Immune Disorders
Stromal Interaction Molecule Deficiency in T Cells Promotes Spontaneous Follicular Helper T Cell Development and Causes Type 2 Immune Disorders
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DOI：
10.4049/jimmunol.1700610
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发表时间：
2019-05
期刊：
影响因子：
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通讯作者：
M. Oh‐hora;Xiuyuan Lu;M. Shiokawa;H. Takayanagi;S. Yamasaki
中科院分区：
文献类型：
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作者：
M. Oh‐hora;Xiuyuan Lu;M. Shiokawa;H. Takayanagi;S. Yamasaki
适当的T细胞反应是由TCR下游的激活和抑制途径之间的严格平衡控制的。虽然TCR信号受损的小鼠或人类会产生自身免疫，但将TCR信号减少与自身免疫联系起来的确切分子机制尚不完全清楚。TCR的参与激活Ca2+信号主要是通过基质相互作用分子（Stim） 1和Stim2激活的储存操作的Ca2+进入。尽管T细胞激活有缺陷，但T细胞中Stim1和Stim2均缺乏的小鼠（条件双敲除[cDKO]）出现淋巴细胞增生性疾病和皮肤炎症，并伴有血清IgG1和IgE水平升高。在cDKO小鼠中，滤泡辅助性T细胞（Tfh）数量显著增加，并自发产生IL-4。cDKO小鼠中IL-4的缺失消除了这些炎症症状。通过进一步删除T细胞中的NFAT2， cDKO小鼠的Tfh发展和炎症症状被消除。这些发现表明，Tfh细胞在缺乏Ca2+信号的情况下自发发育，并引起不调节的2型反应。
Appropriate T cell responses are controlled by strict balance between activatory and inhibitory pathways downstream of TCR. Although mice or humans with impaired TCR signaling develop autoimmunity, the precise molecular mechanisms linking reduced TCR signaling to autoimmunity are not fully understood. Engagement of TCR activates Ca2+ signaling mainly through store-operated Ca2+ entry activated by stromal interaction molecule (Stim) 1 and Stim2. Despite defective T cell activation, mice deficient in both Stim1 and Stim2 in T cells (conditional double knockout [cDKO]) developed lymphoproliferative disorders and skin inflammation with a concomitant increase in serum IgG1 and IgE levels. In cDKO mice, follicular helper T (Tfh) cells were dramatically increased in number, and they produced IL-4 spontaneously. These inflammatory symptoms were abolished by the deletion of IL-4 in cDKO mice. Tfh development and inflammatory symptoms in cDKO mice were abrogated by further deletion of NFAT2 in T cells. These findings suggest that Tfh cells spontaneously developed in the absence of Ca2+ signaling and caused unregulated type 2 responses.