CD4 T cell diversification in the tissue

Heterogeneity is the hallmark feature of CD4 T cells with the ability to differentiate into effector cells of various phenotypes and perform distinct function. This diversification that is essential for optimal response has not been described in the tissue. Using influenza as an infection model, we investigated long-lived antigen-specific CD4 T cells in the tissue. We identified a heterogeneous population of T resident memory cells (TRM) in the tissue, specifically, a T follicular helper-like subset we called T resident helper (TRH) that was previously not reported. Further characterization by single cell RNA sequencing analysis revealed that TRH possess a unique tissue-specific transcriptional signature distinct from lymphoid TFH and that they can be generated independently of lymphoid replenishment. Histological analysis showed that TRH cluster closely with B cells in inducible bronchus-associated lymphoid tissue (iBALT) and require continued BCL6 signaling for their localization. Interestingly, at very late time points, signals through cognate antigen presentation were dispensable for TRH maintenance and iBALT integrity. Upon heterologous challenge, TRH cells support local antibody production highlighting a previously unexplored function of TRM.