Transcriptome analysis of Homo sapiens and Mus musculus reveals mechanisms of CD8+ T cell exhaustion caused by different factors

Abstract

T cell exhaustion is a state of T cell dysfunction during chronic infection and cancer. Antibody-targeting immune checkpoint inhibitors to reverse T cell exhaustion is a promising approach for cancer immunotherapy. However, molecular mechanisms of T cell exhaustion remain incompletely understood. Here, we performed a transcriptome analysis by integrating seven exhaustion datasets caused by multiple diseases in both humans and mice. In this study, an overlap of 21 upregulated and 37 downregulated genes was identified in human and mouse exhausted CD8+ T cells. These genes were significantly enriched in exhaustion response-related pathways, such as signal transduction, immune system processes, and regulation of cytokine production. Gene expression network analysis revealed that the well-documented exhaustion genes were defined as hub genes in upregulated genes. In addition, a weighted gene co-expression analysis identified 175 overlapping genes that were significantly correlated with the exhaustion trait in both humans and mice. This study found that overlapping six genes were significantly upregulated and highly related to T cell exhaustion. Finally, we revealed that CD200R1 and ADGRG1, less described previously in exhaustion, contributed to T cell exhaustion. Overall, our findings reveal the mechanisms of T cell exhaustion and provide an important reference to the immunology community.

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“…. ) were detected [46]. Inversely, the absence of key molecules associated with a highly efficient anti-tumor immune response (IFNG, IL12A and IL12B, IL18, TNF, GNLY, KLRC2, KLRC3, .…”

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“…The expression of genes suppressing immune responses was higher in T cells in the deeply invaded area than in the superficially invaded area; GDF15 , which promotes the generation of Tregs, and GPNMB , which inhibits T‐cell activation, were highly expressed 12,13 . T cells in metastatic lesions exhibited upregulation of genes associated with exhausted T cells, including ADGRG1 , compared to T cells in the vicinity of the primary tumour 14 . Concomitant with these alterations of gene expression levels, the number of tumour‐infiltrating cytotoxic T cells decreased during invasion and metastasis.…”

“…12,13 T cells in metastatic lesions exhibited upregulation of genes associated with exhausted T cells, including ADGRG1, compared to T cells in the vicinity of the primary tumour. 14 Concomitant with these alterations of gene expression levels, the number of tumour-infiltrating cytotoxic T cells decreased during invasion and metastasis. Consistent with the upregulation of M2 polarization genes in melanoma cells during invasion and metastasis, tumour-infiltrating macrophages showed increased expression of FN1, ID3 and MT2A, known inducers of M2 polarization and anti-inflammatory mediator genes (TSC22D3 and FKBP5).…”