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

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