Calcineurin-dependent negative regulation of CD94/NKG2A expression on naive CD8+ T cells
Calcineurin-dependent negative regulation of CD94/NKG2A expression on naive CD8+ T cells
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DOI：
10.1182/blood-2010-11-317396
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发表时间：
2011-07-07
期刊：
影响因子：
20.3
通讯作者：
Sprent, Jonathan
中科院分区：
文献类型：
--
作者：
Cho, Jae-Ho;Kim, Hee-Ok;Sprent, Jonathan
免疫应答导致T细胞上免疫调节分子的表达，包括自然杀伤(NK)受体，如CD8(+)T细胞上的CD94/NKG2A；这些受体抑制CD8(+)反应，从而防止T细胞在慢性感染中耗尽，限制免疫病理。在这里，我们研究了诱导CD94/NKG2A在T细胞上对抗原做出反应的要求。在体外，初始CD8(+)(但不是CD4(+))细胞暴露于CD3结扎或特定的多肽后，CD94/NKG2A的表达被适度诱导。令人惊讶的是，CD28/B7共刺激抑制了CD28/B7的表达。这种抑制作用仅适用于CD94/NKG2A，而不适用于其他NK受体(NKG2D)，并由IL-2介导。IL-2的抑制作用是通过钙调神经磷酸酶途径的NFAT细胞非依赖成分实现的，而在体内外，当存在钙调神经磷酸酶阻滞剂(如FK506)或使用钙调神经磷酸酶缺乏的T细胞时，CD94/NKG2A的诱导显著增强。除了IL-2对CD28依赖的抑制外，CD94/NKG2A的表达还被其他几种细胞因子(IL-4、IL-23和转化生长因子-β)抑制，但被其他细胞因子(IL-6、IL-10和IL-21)增强。这些不同刺激物之间的复杂相互作用可能解释了CD94/NKG2A在体内对不同病原体的反应过程中的不同表达。(血。2011；118(1)：116-128)
Immune responses lead to expression of immunoregulatory molecules on T cells, including natural killer (NK) receptors, such as CD94/NKG2A on CD8(+) T cells; these receptors restrain CD8(+) responses, thereby preventing T-cell exhaustion in chronic infections and limiting immunopathology. Here, we examined the requirements for inducing CD94/NKG2A on T cells responding to antigen. In vitro, moderate induction of CD94/NKG2A expression occurred after exposure of naive CD8(+) (but not CD4(+)) cells to CD3 ligation or specific peptide. Surprisingly, expression was inhibited by CD28/B7 costimulation. Such inhibition applied only to CD94/NKG2A and not other NK receptors (NKG2D) and was mediated by IL-2. Inhibition by IL-2 occurred via a NFAT cell-independent component of the calcineurin pathway, and CD94/NKG2A induction was markedly enhanced in the presence of calcineurin blockers, such as FK506 or using calcineurin-deficient T cells, both in vitro and in vivo. In addition to CD28-dependent inhibition by IL-2, CD94/NKG2A expression was impaired by several other cytokines (IL-4, IL-23, and transforming growth factor-beta) but enhanced by others (IL-6, IL-10, and IL-21). The complex interplay between these various stimuli may account for the variable expression of CD94/NKG2A during responses to different pathogens in vivo. (Blood. 2011;118(1):116-128)