Date of Award
Doctor of Philosophy (PhD)
Cellular, Molecular and Biomedical Sciences
Jonathan E. Boyson
Gamma delta (γδ) T cells are unconventional T cells that are highly enriched in the mucosal tissues such as the lung, gut, and skin, where they play critical roles in host immune surveillance, autoimmunity, and anti-tumor immunity. γδ T cells are notable for their ability to rapidly produce large amounts of cytokines such as IL-17 (γδT17), IFN-γ (γδT1), and IL-4 (γδT2). Interestingly, unlike their well-studied conventional αβ T cell counterparts, most γδ T cells acquire their functional programming during specific developmental windows of thymic development using mechanisms that remain unclear. Here, we investigated the role of the SLAM-SAP signaling pathway in this process, which was recently shown to play a role in the thymic development of innate-like γδT17, γδT1, and γδNKT subsets. We used a single-cell proteogenomics approach coupled with γδ V(D)J profiling to define the transcriptional landscape, TCR repertoire, and developmental checkpoints of SAP-dependent mouse γδ T cells. This analysis confirmed that SLAMF1 and SLAMF6 co-expression profiles marked distinct developmental stages among thymic γδ T cells and also revealed that an additional member of the SLAM family of receptors, SLAMF7, was a marker of mature innate-like CD44+CD45RB+ γδT1 cells in both the thymus and periphery. In addition, analysis of the γδTCR repertoire confirmed that, in addition to the highly restricted γδT17 and γδNKT TCR repertoires, γδT1 subsets were also characterized by expression of a limited set of TCR γ- and δ-chains. Finally, a comparison between B6 and B6.SAP-/- embryonic day 17 (E.17) and neonatal thymic γδ T cells revealed the presence of multiple SAP-dependent developmental checkpoints, including a previously undefined SAP-dependent CD24highCD44posCD73neg developmental checkpoint at embryonic day 17 characterized by the expression of transcription factors/kinases (e.g., Maf, Etv5, and Blk) known to be critical in γδT17 development. Importantly, these SAP-dependent changes in thymic γδ T cell development were associated with significant alterations in the γδT17 TCR repertoire as well as a specific decrease in TRGV4/TRAV13-4(DV7) γδT1 cells in the periphery. Altogether, these data suggest that SLAM-SAP signaling acts during the very early stages of γδ T cell development, where it regulates critical pathways involved in the development of specific γδ T effector subsets and influences the establishment of unique innate-like γδ TCR repertoire in both the thymus and periphery.
Number of Pages
Mistri, Somen Kumar, "The Role Of Slam-Sap Signaling In The Development Of Innate-Like Gamma Delta (γδ) T Cells" (2023). Graduate College Dissertations and Theses. 1665.
Available for download on Wednesday, January 17, 2024