Uncovering the role of STAT5 in CD8+ T cell fate

• Published in: The Journal of immunology (1950) Vol. 210; no. 1_Supplement; pp. 239 - 239.21
• Main Authors: Chanda, Monica Kasturi, Gu, Zehui, Piper, Taylor L, Shudde, Claire E, Courtney, Adam H
• Format: Journal Article
• Language: English
• Published: 01-05-2023
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.210.Supp.239.21

Abstract
Long-term protection against infection and disease requires long-lived memory CD8+ T cells. The development of these memory CD8+ T cells requires a differentiation process influenced by cytokines – such as IL-2, IL-7, and IL-15 – that are known to mediate the balance between effector and memory populations. Interestingly, these cytokines act through the common activation of STAT5, however, the mechanisms by which STAT5 dictates CD8+ T cell fate is poorly understood. To elucidate how STAT5 affects CD8+ T cell differentiation, we have developed a strategy to activate endogenous STAT5 in the absence of cytokine. We compared CD8+ T cells cultured in IL-2, a cytokine known to promote effector CD8+ T cells, to those where STAT5 was directly activated. We found that direct activation of STAT5 resulted in decreased IFNγ production in comparison to IL-2 treatment. This observation led us to evaluate the expression of transcription factors and proteins related to effector, memory, and exhausted states. Our results demonstrate that CD8+ T cells that experience direct activation of STAT5 have higher levels of TCF1 and lower levels of granzyme B compared to CD8+ T cells cultured in IL-2. To gain an understanding of phenotypic changes and differentiation state, we performed bulk RNA sequencing to assess global changes in gene expression. Our RNA sequencing results indicate that when compared to CD8+ T cells cultured in IL-2, direct STAT5 activation causes increased expression of genes related to a memory phenotype and a corresponding decrease in those related to an effector or exhausted phenotype. Our findings suggest that STAT5 activation is critical to a memory-like phenotype and could be harnessed for therapeutic benefit in CD8+ T cell-based treatments.
Supported by grants from the V Foundation and the Concern Foundation