Portrayed the development of activated T cell to exhausted T cell based on the ratio of CD28 to CTLA4.

T cell exhaustion, to some extent, limits the clearance of viruses and tumor cells and accounts for the poor effectiveness of immune therapy. The generally accepted classification of exhausted T cells assigns them as progenitor and terminal statuses. However, the outcome of immune therapy benefits little from this classification. In this study, we constructed a new indicator with the ratio of CD28 to CTLA4 (ccRatio) to continuously characterize the development of T cell from activation to exhaustion. We showed that the ccRatio decreased as T cell exhaustion progressed. We also found that patients who benefitted from anti-CTLA4 treatment had a higher ccRatio value. In addition, by studying the genes that correlated with ccRatio, we found ccRatio is associated with T cell functions which is further confirmed in validation datasets. Furthermore, we found that transcription factor VDR can contribute to differentiation of T cell from activation to exhaustion. The establishment of ccRatio allows us to study T cell exhaustion in a continuous developmental perspective, which is conducive to understand the T cell differentiation and helped in improving existing immunotherapy methods.