Effector TH17 cells give rise to long-lived TRM cells that are essential for an immediate response against bacterial infection

Mucosal barrier surfaces serve as the critical first line of defense separating our bodies from the plethora of pathogenic microorganisms that inhabit our environment. Adaptive immunity provides life-long protection through the generation of a central and effector memory T-cell pool, memory B cells and the recently described population of tissue resident memory cells (TRM). The cellular origin of TRM CD4 cells is unknown and the contribution of this CD4 memory population to host defense still remains elusive. By using IL-17A tracking-fate-mouse models we found that a significant fraction of the CD4 TRM cells derive from IL-17A producing effector (TH17) cells following primary immunization. Maintenance of these resting exTH17 TRM cells is mediated by IL-7, produced by lymphatic endothelial cells. During a memory response, we show that neither antibodies, nor gd T cells, nor circulatory memory T cells are sufficient for the rapid host defense required to eliminate the pathogen. Using parabiosis and depletion studies, we demonstrated that CD4 exTH17 TRM cells play an important role in respiratory defense and bacterial clearance. Upon infection, exTH17 TRM cells rapidly produce IL-17A and IFN-γ to promote neutrophil infiltration and bacterial clearance. These studies delineate the origin, function and importance of airway CD4 TRM cells during bacterial infection, offering novel strategies for targeted vaccine design, which is especially imperative for those pathogens that are resistant to antibiotic treatment. We profiled the transcriptome of draining lymph node (LN) naïve CD4 T cells (2 replicates), memory CD4 T cells (2 replicates) and the 3 populations of TRM cells present in the lung 35 days after immunization with heat-killed Klebsiella pneumoniae (TH17, exTH17 (3 replicates) and YFPneg (2 replicates)).