Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Cell Mol Immunol. 2021 Oct;18(10):2410-2421. doi: 10.1038/s41423-020-0495-7. Epub 2020 Jul 1.
Acute viral infection causes illness and death. In addition, an infection often results in increased susceptibility to a secondary infection, but the mechanisms behind this susceptibility are poorly understood. Since its initial identification as a marker for resident memory CD8 T cells in barrier tissues, the function and regulation of CD103 integrin (encoded by ITGAE gene) have been extensively investigated. Nonetheless, the function and regulation of the resident CD103CD8 T cell response to acute viral infection remain unclear. Although TGFβ signaling is essential for CD103 expression, the precise molecular mechanism behind this regulation is elusive. Here, we reveal a TGFβ-SKI-Smad4 pathway that critically and specifically directs resident CD103CD8 T cell generation for protective immunity against primary and secondary viral infection. We found that resident CD103CD8 T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice. CD103 acts as a costimulation signal to produce an optimal antigenic CD8 T cell response to acute viral infection. There is a reduction in resident CD103CD8 T cells following primary infection that results in increased susceptibility of the host to secondary infection. Intriguingly, CD103 expression inversely and specifically correlates with SKI proto-oncogene (SKI) expression but not R-Smad2/3 activation. Ectopic expression of SKI restricts CD103 expression in CD8 T cells in vitro and in vivo to hamper viral clearance. Mechanistically, SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner. Our study therefore reveals that resident CD103CD8 T cells dictate protective immunity during primary and secondary infection. Interfering with SKI function may amplify the resident CD103CD8 T cell response to promote protective immunity.
急性病毒感染可导致发病和死亡。此外，感染通常会导致机体对二次感染的易感性增加，但这种易感性的机制尚不清楚。自最初将 CD103 整合素（由 ITGAE 基因编码）鉴定为屏障组织中常驻记忆 CD8 T 细胞的标志物以来，其功能和调节已得到广泛研究。尽管 TGFβ 信号对于 CD103 的表达是必需的，但这种调节的精确分子机制尚不清楚。在这里，我们揭示了一个 TGFβ-SKI-Smad4 通路，该通路对于急性病毒感染中常驻 CD103CD8 T 细胞的产生和保护性免疫至关重要。我们发现，未感染小鼠的淋巴和非淋巴组织中均存在丰富的常驻 CD103CD8 T 细胞。CD103 作为共刺激信号，可产生针对急性病毒感染的最佳抗原 CD8 T 细胞反应。初次感染后常驻 CD103CD8 T 细胞减少，导致宿主对二次感染的易感性增加。有趣的是，CD103 的表达与 SKI 原癌基因（SKI）的表达呈反比且特异性相关，但与 R-Smad2/3 的激活无关。SKI 的异位表达可在体外和体内限制 CD8 T 细胞中 CD103 的表达，从而阻碍病毒清除。从机制上讲，SKI 被募集到 Itgae 基因座，通过依赖 Smad4 的方式调节组蛋白乙酰化来直接抑制 CD103 转录。因此，我们的研究表明，常驻 CD103CD8 T 细胞决定了初次和二次感染期间的保护性免疫。干扰 SKI 功能可能会增强常驻 CD103CD8 T 细胞的反应，以促进保护性免疫。
