The transcriptional corepressor Tle (transducin-like enhancer of split) proteins interact with transcription factors such as TCF-1 and Runx3 to regulate transcriptional programmes during cellular development and differentiation; however, their roles in CD8+ T cell differentiation, particularly under conditions of chronic antigen stimulation, remain poorly defined. Here, we demonstrated that overexpression of Tle1, Tle3, and Tle4 improves the proliferation of antigen-specific effector CD8+ T cells during both acute and chronic viral infections. Notably, overexpression of Tle3 and Tle4, but not Tle1, augmented secondary responses of memory CD8+ T cells in the context of acute viral infection. Tle1-overexpressing CD8+ T cells displayed enhanced TCR signal strength, accompanied by elevated expression of immunoinhibitory receptors such as PD-1 and LAG-3. Transcriptome analyses and genome-wide binding profiles suggested that Tle1 and Tle3 cooperate with multiple transcription factors, including members of the Ets, AP-1, and Runx families, to drive expression of genes involved in the activation and maintenance of antigen-specific CD8+ T cell responses. Notably, Tle1 overexpression improves cytotoxic T lymphocyte (CTL) responses to PD-1/PD-L1 blockade during chronic viral infection. Tle1 was found to enhance TCR signalling and the expression of immunoinhibitory receptors through repression of TCF-1, whereas its effect on effector CD8+ T cell proliferation occurred independently of TCF-1. These findings revealed the regulatory roles of Tle proteins in orchestrating transcription factor networks that govern CD8+ T cell differentiation during viral infections.
Shiga et al. (Wed,) studied this question.