Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA 95616.
Division of Experimental Medicine, Department of Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California San Francisco, San Francisco, CA 94110.
J Immunol. 2018 Mar 1;200(5):1876-1888. doi: 10.4049/jimmunol.1701532. Epub 2018 Jan 19.
We previously reported that CD8 T cells in human gastrointestinal mucosa exhibit reduced perforin expression and weak or impaired cytotoxic capacity compared with their counterparts in blood. Nevertheless, these cells degranulate and express cytokines and chemokines in response to cognate Ag. In addition to weak expression of perforin, earlier studies suggested differential regulation of perforin and granzymes (Gzms), with GzmA and B expressed by significantly higher percentages of mucosal CD8 T cells than perforin. However, this topic has not been fully explored. The goal of this study was to elucidate the expression and coexpression patterns of GzmA, B, and K in conjunction with perforin in rectosigmoid CD8 T cells during HIV-1 infection. We found that expression of both perforin and GzmB, but not GzmA or GzmK, was reduced in mucosa compared with blood. A large fraction of rectosigmoid CD8 T cells either did not express Gzms or were single-positive for GzmA. Rectosigmoid CD8 T cells appeared skewed toward cytokine production rather than cytotoxic responses, with cells expressing multiple cytokines and chemokines generally lacking in perforin and Gzm expression. These data support the interpretation that perforin and Gzms are differentially regulated, and display distinct expression patterns in blood and rectosigmoid T cells. These studies may help inform the development of strategies to combat HIV-1 and other mucosal pathogens.
我们之前报道过，与血液中的细胞相比，人类胃肠道黏膜中的 CD8 T 细胞表现出穿孔素表达减少和细胞毒性能力减弱或受损。然而，这些细胞在响应同源 Ag 时会脱颗粒并表达细胞因子和趋化因子。除了穿孔素表达较弱外，早期研究还表明穿孔素和颗粒酶（Gzms）的调节存在差异，黏膜 CD8 T 细胞中 GzmA 和 B 的表达百分比明显高于穿孔素。然而，这个话题尚未得到充分探讨。本研究的目的是阐明 HIV-1 感染期间直肠乙状结肠 CD8 T 细胞中穿孔素与 GzmA、B 和 K 的表达和共表达模式。我们发现，与血液相比，黏膜中穿孔素和 GzmB 的表达均降低，而 GzmA 或 GzmK 的表达则没有降低。直肠乙状结肠 CD8 T 细胞中很大一部分既不表达 Gzms，也不表达 GzmA。直肠乙状结肠 CD8 T 细胞似乎偏向于细胞因子产生，而不是细胞毒性反应，表达多种细胞因子和趋化因子的细胞通常缺乏穿孔素和 Gzm 表达。这些数据支持这样的解释，即穿孔素和 Gzms 受到不同的调节，并在血液和直肠乙状结肠 T 细胞中表现出不同的表达模式。这些研究可能有助于为对抗 HIV-1 和其他黏膜病原体的策略提供信息。
