Mani Rajesh, Balu Kanal E, Suzuki Yasuhiro
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA.
Cells. 2024 Dec 3;13(23):1998. doi: 10.3390/cells13231998.
We recently identified that the cerebral mRNA expression of inducible costimulator (ICOS) and its ligand, ICOSL, both significantly increase during the elimination of cysts from the brains of infected mice by the perforin-mediated cytotoxic activity of CD8 T cells. In the present study, we examined the role of ICOS in activating the effector activity of CD8 T cells in response to the presence of cysts in infected mice. Following the adoptive transfer of splenic CD8 T cells from chronically infected ICOS-deficient (ICOS) and wild-type (WT) mice to infected SCID mice, fewer CD8 T cells were detected in the brains of the recipients of ICOS CD8 T cells than the recipients of WT CD8 T cells. Interestingly, even with the lower migration rate of the ICOS CD8 T cells, those T cells eliminated cysts more efficiently than WT CD8 T cells did in the brains of the recipient mice. Consistently, the ICOS CD8 T cells secreted greater amounts of granzyme B in response to antigens in vitro than WT CD8 T cells did. We identified that CD8 T cells of infected ICOS mice express significantly greater levels of CD28 on their surface than CD8 T cells of infected WT mice, and the relative expression of CD28 mRNA to CD8β mRNA levels in the brains of the recipients of those CD8 T cells were strongly correlated with their relative expression levels of mRNA for T-bet transcription factors and perforin. Furthermore, blocking CD28 signaling using a combination of anti-CD80 and anti-CD86 antibodies eliminated the increased cytotoxic activity of the ICOS CD8 T cells in vitro. The present study uncovered notable compensatory interactions between ICOS and CD28, which protected the cytotoxic effector activity of CD8 T cells against microbial infection in a murine model of chronic infection with .
我们最近发现，在通过CD8 T细胞穿孔素介导的细胞毒性活性清除感染小鼠脑内囊肿的过程中，诱导性共刺激分子（ICOS）及其配体ICOSL的脑内mRNA表达均显著增加。在本研究中，我们检测了ICOS在激活感染小鼠体内针对囊肿的CD8 T细胞效应活性中的作用。将慢性感染的ICOS缺陷（ICOS）小鼠和野生型（WT）小鼠的脾CD8 T细胞过继转移至感染的SCID小鼠后，与WT CD8 T细胞受体相比，ICOS CD8 T细胞受体的脑内检测到的CD8 T细胞更少。有趣的是，即使ICOS CD8 T细胞的迁移率较低，但在受体小鼠脑内，这些T细胞比WT CD8 T细胞更有效地清除了囊肿。同样，在体外，ICOS CD8 T细胞对抗抗原时分泌的颗粒酶B比WT CD8 T细胞更多。我们发现，感染ICOS小鼠的CD8 T细胞表面CD28的表达水平显著高于感染WT小鼠的CD8 T细胞，并且这些CD8 T细胞受体脑内CD28 mRNA与CD8β mRNA水平的相对表达与T-bet转录因子和穿孔素mRNA的相对表达水平密切相关。此外，使用抗CD80和抗CD86抗体组合阻断CD28信号，消除了ICOS CD8 T细胞在体外增强的细胞毒性活性。本研究揭示了ICOS与CD28之间显著的代偿性相互作用，在慢性感染的小鼠模型中保护了CD8 T细胞针对微生物感染的细胞毒性效应活性。
