TCF-1 dictates lung tissue resident helper T cell and memory B cell development during flu

Abstract Influenza (flu) infections are a significant cause of annual human morbidity and mortality. The efficacy of seasonal flu vaccines depends on the accuracy of the prediction of the circulating strains for the upcoming season. To develop flu vaccines that are broadly effective and more sustainable, induction of a cross-reactive memory immunity is desirable. Flu infection induces cross-reactive tissue resident memory T (Trm) and B (Brm) cells which rapidly respond to reinfection. Tissue resident helper T (Trh) cells are a population of T follicular helper (Tfh)-like CD4 +Trm cells that promote the development of Brm cell responses following flu infection. The transcription factor TCF-1, encoded by Tcf7, is critical in the development of both memory T cells and Tfh cells following viral infections. However, the role of TCF-1 in Trh cell development has not been investigated. Utilizing a Tcf7 fl/flCD4 Creconditional knockout mouse model in conjunction with intravascular labeling and influenza A peptide MHC Class II tetramers, we found that TCF-1 is required for the differentiation of flu-specific Trh cells, as well as optimal Brm development following flu infections. Most significantly, upon heterosubtypic reinfection, the Trh population in the Tcf7 fl/flcontrol mice expanded while it became undetectable in the Tcf7 fl/flCD4 Cremice, coinciding with a severely impaired lung resident germinal center B cell and CD138 +plasma cell response. Together, our data indicates that TCF-1 is critical in the development of lung tissue resident helper cells and tissue resident memory B cell response following flu infections. This work has implications for the development of universal flu vaccines.