IL-15 supports the generation of protective lung-resident memory CD4 T cells

Tissue-resident memory T cells (T-RM) provide optimal defense at the sites of infection, but signals regulating their development are unclear, especially for CD4 Tcells. Here we identify two distinct pathways that lead to the generation of CD4T(RM) in the lungs following influenza infection. The T-RM are transcriptionally distinct from conventional memoryCD4T cells and share a gene signature with CD8 T-RM. The CD4 T-RM are superior cytokine producers compared with conventional memory cells, can protect otherwise naive mice against a lethal influenza challenge, and display functional specialization by inducing enhanced inflammatory responses from dendritic cells compared with conventional memory cells. Finally, we demonstrate than an interleukin (IL)-2-dependent and a novel IL-2-independent but IL-15-dependent pathway support the generation of cohorts of lung T-RM.