T-bet optimizes CD4 T-cell responses against influenza through CXCR3-dependent lung trafficking but not functional programming.,Mucosal Immunology

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T-bet optimizes CD4 T-cell responses against influenza through CXCR3-dependent lung trafficking but not functional programming.
Mucosal Immunology ( IF 7.9 ) Pub Date : 2019-07-05 , DOI: 10.1038/s41385-019-0183-z
Kunal Dhume ₁ , Caroline M Finn ₁ , Tara M Strutt _{1,

2} , Stewart Sell ₃ , K Kai McKinstry _{1,

2}

Affiliation

Although clearance of many intracellular pathogens requires T-bet-dependent CD4 T cell programming, the extent to which T-bet is needed to direct protective CD4 responses against influenza is not known. Here, we characterize wild-type and T-bet-deficient CD4 cells during murine influenza infection. Surprisingly, although T-bet expression has broad impacts on cytokine production by virus-specific CD4 cells, the protective efficacy of T-bet-deficient effector cells is only marginally reduced. This reduction is due to lower CXCR3 expression, leading to suboptimal accumulation of activated T-bet-deficient cells in the infected lung. However, T-bet-deficient cells outcompete wild-type cells to form lung-resident and circulating memory populations following viral clearance, and primed T-bet-deficient mice efficiently clear supralethal heterosubtypic influenza challenges even when depleted of CD8 T cells. These results are relevant to the identification of more incisive correlates of protective T cells and for vaccines that aim to induce durable cellular immunity against influenza.

中文翻译：

T-bet 通过 CXCR3 依赖性肺运输而非功能编程优化 CD4 T 细胞对流感的反应。

虽然许多细胞内病原体的清除需要 T-bet 依赖性 CD4 T 细胞编程，但 T-bet 在多大程度上需要指导针对流感的保护性 CD4 反应尚不清楚。在这里，我们描述了小鼠流感感染期间的野生型和 T-bet 缺陷型 CD4 细胞。令人惊讶的是，虽然 T-bet 表达对病毒特异性 CD4 细胞的细胞因子产生具有广泛影响，但 T-bet 缺陷效应细胞的保护功效仅略微降低。这种减少是由于较低的 CXCR3 表达，导致受感染肺中活化的 T-bet 缺陷细胞的次优积累。然而，在病毒清除后，T-bet 缺陷细胞在竞争中胜过野生型细胞，形成肺部驻留和循环记忆群体，和引发的 T-bet 缺陷小鼠即使在 CD8 T 细胞耗尽时也能有效清除超致死异亚型流感挑战。这些结果与保护性 T 细胞的更深刻相关性的鉴定以及旨在诱导针对流感的持久细胞免疫的疫苗有关。

更新日期：2019-11-18

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