The adaptor molecule CD2AP in CD4 T cells modulates differentiation of follicular helper T cells during chronic LCMV infection.
The adaptor molecule CD2AP in CD4 T cells modulates differentiation of follicular helper T cells during chronic LCMV infection.
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DOI：
10.1371/journal.ppat.1007053
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发表时间：
2018-05
期刊：
影响因子：
6.7
通讯作者：
Egawa T
中科院分区：
文献类型：
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作者：
Raju S;Kometani K;Kurosaki T;Shaw AS;Egawa T
CD4T细胞介导的对CD8T细胞和B细胞的帮助是控制病原体感染所需的适应性免疫系统的关键。CD4T细胞表达细胞因子和共刺激分子，支持持续的CD8T细胞反应，并促进生发中心B细胞产生保护性抗体。然而，调节CD4T细胞功能的分子成分对病毒感染或疫苗的反应还不完全清楚。在这里，我们证明了信号适配器CD2相关蛋白(CD2AP)的失活促进了CD4T细胞向滤泡辅助谱系的分化，从而通过增强慢性淋巴细胞性脉络膜脑膜炎病毒(LCMV)感染的生发中心反应来增强对病毒感染的控制。在TH1条件下，TCR信号持续时间的延长和CD2AP缺陷的CD4T细胞产生细胞因子的增加与卵泡辅助分化的增强有关，而在诱导其他辅助效应亚群的条件下，TCR信号的延长和卵泡辅助分化的增强都没有观察到。尽管CD2AP和密切相关的接头蛋白CIN85在结构上相似，但我们观察到在T细胞中缺乏CIN85的小鼠中，抗体介导的慢性LCMV感染的控制存在缺陷，这表明CD2AP和CIN85的作用不重叠，可能具有拮抗作用。这些结果表明，通过靶向CD2AP调节TCR信号可以改善病毒感染中的保护性抗体反应。加强对感染或疫苗的保护性抗体的产生对宿主保护至关重要。然而，我们对增强CD4辅助T细胞功能的分子靶点的了解有限，这些功能对于抗体亲和力成熟和类别转换是必不可少的。在这项工作中，我们发现抑制接头分子CD2AP的功能会导致抗体反应增强，并改善对小鼠免受LCMV慢性感染的保护。缺乏T细胞特异性CD2AP的小鼠表现出增强的CD4T细胞向滤泡辅助亚群的分化，滤泡辅助亚群是抗体反应的关键调节因素，并产生更多生发中心B细胞，导致产生突变的保护性抗体。CD2AP缺失对II型免疫应答中的CD4T细胞或CD8T细胞影响不大。因此，我们的结果表明，CD2AP可以作为在病毒感染或疫苗接种过程中增强抗病毒保护性免疫的特异性靶点。
CD4 T cell-mediated help to CD8 T cells and B cells is a critical arm of the adaptive immune system required for control of pathogen infection. CD4 T cells express cytokines and co-stimulatory molecules that support a sustained CD8 T cell response and also enhance generation of protective antibody by germinal center B cells. However, the molecular components that modulate CD4 T cell functions in response to viral infection or vaccine are incompletely understood. Here we demonstrate that inactivation of the signaling adaptor CD2-associated protein (CD2AP) promotes CD4 T cell differentiation towards the follicular helper lineage, leading to enhanced control of viral infection by augmented germinal center response in chronic lymphocytic choriomeningitis virus (LCMV) infection. The enhanced follicular helper differentiation is associated with extended duration of TCR signaling and enhanced cytokine production of CD2AP-deficient CD4 T cells specifically under TH1 conditions, while neither prolonged TCR signaling nor enhanced follicular helper differentiation was observed under conditions that induce other helper effector subsets. Despite the structural similarity between CD2AP and the closely related adaptor protein CIN85, we observed defective antibody-mediated control of chronic LCMV infection in mice lacking CIN85 in T cells, suggesting non-overlapping and potentially antagonistic roles for CD2AP and CIN85. These results suggest that tuning of TCR signaling by targeting CD2AP improves protective antibody responses in viral infection. Enhancing the production of protective antibodies in response to infection or vaccine is critically important for host protection. However, we have only limited knowledge about molecular targets to enhance functions of CD4 helper T cells that are essential for antibody affinity maturation and class switching. In this work, we found that inhibiting the function of the adaptor molecule CD2AP results in enhanced antibody responses and improved protection of mice from chronic infection by LCMV. Mice lacking CD2AP specifically in T cells showed enhanced CD4 T cell differentiation towards the follicular helper subset, which is a critical regulator of antibody responses, and generated more germinal center B cells leading to production of mutated, protective antibodies. This effect was specific to CD4 T cells in type-I immune responses, associated with viral infection, while deletion of CD2AP had little impact on CD4 T cells in type-II immune responses or CD8 T cells. Our results thus suggest that CD2AP can be a specific target to enhance antiviral protective immunity during viral infection or vaccination.
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影响因子：
3.7
作者：
Bretscher PA
通讯作者：
Bretscher PA
DOI：
10.1084/jem.20101773
发表时间：
2011-05-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fahey LM;Wilson EB;Elsaesser H;Fistonich CD;McGavern DB;Brooks DG
通讯作者：
Brooks DG
DOI：
10.1084/jem.20102665
发表时间：
2011-07-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kometani K;Yamada T;Sasaki Y;Yokosuka T;Saito T;Rajewsky K;Ishiai M;Hikida M;Kurosaki T
通讯作者：
Kurosaki T
DOI：
10.1073/pnas.1401662111
发表时间：
2014-05-20
影响因子：
11.1
作者：
Osokine, Ivan;Snell, Laura M.;Brooks, David
通讯作者：
Brooks, David
影响因子：
30.5
作者：
通讯作者：
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