Roles of transcription factor T-bet in memory CD4+ T cell generation, function, homeostasis and tissue targeting

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Memory T cells are a critical component of immunological memory, which provides long-lasting immunological protection. These cells are characterized by a lower response threshold, rapid effector cytokine production, and prolonged longevity, and thus allow organisms to respond to pathogens more rapidly and effectively. However, the mechanisms that regulate the generation, function, homeostasis and tissue targeting of memory CD4+ T cells are not clear. This body of work investigated post-effector requirement for T-bet expression in determining the circulating and tissue resident memory CD4+ T cell fate and the implications of early T-bet deletion on lung CD4+ TRM development. We used mouse models with conditional expression of T-bet to delete T-bet in CD4+ T cells after priming and effector differentiation to analyze the development of resultant memory CD4+ T cells. We found that T-bet-ablation following cell priming and Th1 polarization did not impair the ability of Th1 effector cells to produce high levels of IFN-γ production, and moreover, there were dramatic increases in IL-2 production, suggesting post-effector T-bet expression is not required for functional maintenance in effector cells. Memory CD4+ T cells that developed from T-bet ablated effector cells after transfer to lymphocyte deficient RAG1/2-/- hosts or intact congenic hosts had increased persistence, and they maintained lower but substantial levels of IFN-γ and higher IL-2 production. We found elevation of IL-17 production and RORγt expression in T-bet ablated memory CD4+ T cells, and transcriptome analysis further showed that these cells upregulated genes expressed by other CD4+ T cell subsets, including Foxp3 and GATA3, indicating greater functional plasticity of T-bet-ablated memory CD4+ T cells. Increased localization of T-bet-ablated memory CD4+ T cells in the lung resident niche was found only in RAG1/2-/- hosts but not in congenic hosts, indicating the importance of the tissue environment in the development of TRM cells. Using antigen specific T-bet+/- OT-II and T-bet-/- OT-II cells, we found that T-bet+/- OT-II cells had increased persistence while T-bet-/- OT-II cells had decreased persistence compared with the wild type OT-II cells after PR8-OVA influenza virus infection. However, both T-bet+/- and T-bet-/- OT-II cells had normal TRM formation. Collectively, our results reveal the roles of T-bet in regulating the generation, function, maintenance and tissue targeting of memory CD4+ T cells.