Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
J Exp Med. 2013 Jul 29;210(8):1591-601. doi: 10.1084/jem.20130097. Epub 2013 Jul 8.
CD4(+) T cells promote CD8(+) T cell priming by licensing dendritic cells (DCs) via CD40-CD154 interactions. However, the initial requirement for CD40 signaling may be replaced by the direct activation of DCs by pathogen-derived signals. Nevertheless, CD40-CD154 interactions are often required for optimal CD8(+) T cell responses to pathogens for unknown reasons. Here we show that CD40 signaling is required to prevent the premature contraction of the influenza-specific CD8(+) T cell response. CD40 is required on DCs but not on B cells or T cells, whereas CD154 is required on CD4(+) T cells but not CD8(+) T cells, NKT cells, or DCs. Paradoxically, even though CD154-expressing CD4(+) T cells are required for robust CD8(+) T cell responses, primary CD8(+) T cell responses are apparently normal in the absence of CD4(+) T cells. We resolved this paradox by showing that the interaction of CD40-bearing DCs with CD154-expressing CD4(+) T cells precludes regulatory T cell (T reg cell)-mediated suppression and prevents premature contraction of the influenza-specific CD8(+) T cell response. Thus, CD4(+) T helper cells are not required for robust CD8(+) T cell responses to influenza when T reg cells are absent.
CD4(+) T 细胞通过 CD40-CD154 相互作用来许可树突状细胞 (DC)，从而促进 CD8(+) T 细胞的初始激活。然而，DC 被病原体衍生的信号直接激活，可能会取代 CD40 信号的初始要求。尽管如此，由于未知原因，CD40-CD154 相互作用通常是病原体引发的 CD8(+) T 细胞反应的最佳反应所必需的。在这里，我们表明 CD40 信号传导对于防止流感特异性 CD8(+) T 细胞反应的过早收缩是必需的。CD40 信号传导需要在 DC 上，但不需要在 B 细胞或 T 细胞上，而 CD154 需要在 CD4(+) T 细胞上，但不需要在 CD8(+) T 细胞、NKT 细胞或 DC 上。矛盾的是，尽管表达 CD154 的 CD4(+) T 细胞对于强烈的 CD8(+) T 细胞反应是必需的，但在没有 CD4(+) T 细胞的情况下，初级 CD8(+) T 细胞反应显然是正常的。我们通过表明 CD40 阳性 DC 与表达 CD154 的 CD4(+) T 细胞之间的相互作用排除了调节性 T 细胞 (Treg 细胞)介导的抑制作用，并防止了流感特异性 CD8(+) T 细胞反应的过早收缩，从而解决了这一矛盾。因此，当不存在 Treg 细胞时，CD4(+) T 辅助细胞对于流感的强烈 CD8(+) T 细胞反应并不是必需的。
