A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells

CD8 tissue-resident memory T (T(RM)) cells provide efficient local control of viral infection, but the role of CD4 T(RM) is less clear. Here, by using parabiotic mice, we show that a preexisting pool of CD4 T(RM) cells in the genital mucosa was required for full protection from a lethal herpes simplex virus 2 (HSV-2) infection. Chemokines secreted by a local network of macrophages maintained vaginal CD4 T(RM) in memory lymphocyte clusters (MLCs), independently of circulating memory T cells. CD4 T(RM) cells within the MLCs were enriched in clones that expanded in response to HSV-2. Our results highlight the need for vaccine strategies that enable establishment of T(RM) cells for protection from a sexually transmitted virus and provide insights as to how such a pool might be established.