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Asymmetry and redundancy of STAT5 paralogs across CD8+ T cell differentiation states
Svetlana Ristin1,2, Molly Dalzell1,2, Christopher Armstrong1
1Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA.
Abstract:
Fostering STAT5 signaling is key to immunotherapies that leverage CD8+ T cell biology. Using mouse models, we demonstrate that the two mammalian STAT5 paralogs, STAT5A and STAT5B, are at once redundant and functionally distinct in CD8+ T cells. Specifically, we establish that they are asymmetric paralogs, exhibiting both widespread homology at molecular level and functional asymmetry at cellular level, with STAT5B emerging as dominant. In fact, compared to STAT5A, STAT5B deficiency had greater impact on nearly all parameters tested. As a mechanism, we determined STAT5B is twice as abundant, accounting for two-thirds of the total STAT5 pool. We also defined both cytokine- and cell state-restricted STAT5B functions, and a core gene signature that highlights universal effects. Together, these studies affirm the centrality of STAT5 in CD8+ T cells, reveal common and circumscribed activities, and present a unifying model for paralog redundancy that foregrounds and explains the dominance of STAT5B.
Insights
Signal transducer and activator of transcription 5 (STAT5) signaling is crucial for CD8+ T cell immunotherapy. STAT5B is the dominant paralog, showing greater impact than STAT5A due to higher abundance and distinct functions.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Signal transducer and activator of transcription 5 (STAT5) signaling is critical for CD8+ T cell function in immunotherapy.
- The two mammalian STAT5 paralogs, STAT5A and STAT5B, play roles in T cell biology.
Purpose of the Study:
- To investigate the distinct and overlapping functions of STAT5A and STAT5B in CD8+ T cells.
- To elucidate the mechanisms underlying the dominance of STAT5B in CD8+ T cell responses.
Main Methods:
- Utilized mouse models to study STAT5 paralog function in CD8+ T cells.
- Analyzed STAT5 paralog abundance, cytokine-dependent functions, and cell state-specific activities.
- Defined a core gene signature associated with STAT5 activity.
Main Results:
- STAT5A and STAT5B are functionally distinct yet partially redundant in CD8+ T cells, acting as asymmetric paralogs.
- STAT5B is the dominant paralog, accounting for two-thirds of the total STAT5 pool and exhibiting greater impact on T cell parameters.
- Identified cytokine- and cell state-restricted functions for STAT5B and a universal gene signature.
Conclusions:
- STAT5B plays a dominant role in CD8+ T cell biology, influencing various cellular functions.
- The findings provide a unifying model for paralog redundancy, highlighting the importance of STAT5B.
- Understanding STAT5 paralog function is key for optimizing immunotherapies involving CD8+ T cells.
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