Blockade of CTLA-4 Decreases the Generation of Multifunctional Memory CD4+ T Cells In Vivo
Blockade of CTLA-4 Decreases the Generation of Multifunctional Memory CD4+ T Cells In Vivo
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DOI：
10.4049/jimmunol.1003381
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发表时间：
2011-05-15
影响因子：
4.4
通讯作者：
Brunner-Weinzierl, Monika C.
中科院分区：
文献类型：
--
作者：
Rudolph, Marion;Hebel, Katrin;Brunner-Weinzierl, Monika C.
CTLA-4被认为是T细胞反应的中枢抑制因子。它终止T细胞的激活和增殖，并诱导抵抗激活引起的细胞死亡。然而，它对获得性免疫反应记忆形成的影响仍不清楚。在这项研究中，我们证明，尽管在小鼠初次免疫期间进行抗CTLA-4单抗治疗，最初会增加产生干扰素-伽马的CD4(+)T细胞的数量，但它不影响记忆池的大小。有趣的是，我们发现CTLA-4的阻断调节了内存池的质量：它减少了专门的“多功能”记忆CD4(+)T细胞的数量，共同产生干扰素-伽马、肿瘤坏死因子-α和白介素2来响应抗原。在体内抗原再攻击后，这些细胞的减少会导致产生干扰素-γ的T细胞的大量减少。表达CTLA-4活性细胞和缺陷细胞的嵌合小鼠揭示了这些CTLA-4驱动的机制是非自主地介导CD4(+)T细胞。此外，在产生抗原特异性记忆细胞之前，CD25(+)T细胞的耗尽表明，结构性表达CTLA-4的自然调节性T细胞决定了记忆CD4(+)T细胞的质量。综上所述，这些结果表明，尽管抑制分子CTLA-4抑制了初级免疫反应，但它的参与对高质量记忆池的形成起到了积极的调节作用，该记忆池配备了多功能的CD4(+)T细胞，能够对抗原再攻击产生强大的反应。免疫学杂志，2011,186：5580-5589。
CTLA-4 is known as a central inhibitor of T cell responses. It terminates T cell activation and proliferation and induces resistance against activation induced cell death. However, its impact on memory formation of adaptive immune responses is still unknown. In this study, we demonstrate that although anti-CTLA-4 mAb treatment during primary immunization of mice initially enhances the number of IFN-gamma-producing CD4(+) T cells, it does not affect the size of the memory pool. Interestingly, we find that the CTLA-4 blockade modulates the quality of the memory pool: it decreases the amount of specialized "multifunctional" memory CD4(+) T cells coproducing IFN-gamma, TNF-alpha, and IL-2 in response to Ag. The reduction of these cells causes an immense decrease of IFN-gamma-producing T cells after in vivo antigenic rechallenge. Chimeric mice expressing CTLA-4-competent and -deficient cells unmask, which these CTLA-4-driven mechanisms are mediated CD4(+) T cell nonautonomously. In addition, the depletion of CD25(+) T cells prior to the generation of Ag-specific memory cells reveals that the constitutively CTLA-4-expressing natural regulatory T cells determine the quality of memory CD4(+) T cells. Taken together, these results indicate that although the inhibitory molecule CTLA-4 damps the primary immune response, its engagement positively regulates the formation of a high-quality memory pool equipped with multifunctional CD4(+) T cells capable of mounting a robust response to Ag rechallenge. The Journal of Immunology, 2011, 186: 5580-5589.