CD4+ T cells have long been known to play an important role in the immune response to skin infection with Leishmania major. However, the role of permanently skin-resident cells in immune protection has not been explored in any detail, with the majority of studies implicitly assuming that all the memory cells recirculate back to the blood. In this issue, Glennie et al. report that skin-resident CD4+ T cells are critical for optimal immune control of Leishmania due to their ability to recruit circulating cells to the site of infection.
Tissue-resident memory T cells (TRM) are a nonrecirculating subset of T cells that provide local immune protection from reinfection. Although the majority of TRM studies have focused on CD8+ T cells, their CD4+ counterparts have received less attention, and the role of TRM in protection against parasitic infection has not been explored. After L. major infection, Glennie et al. identify a population of CD4+ T cells that remains in the skin, including sites distal to primary inoculation, for up to a year after infection. At least a proportion of these cells were long-term residents in the tissue, as they persisted in the skin after transplantation onto naive animals. Importantly, L. major–specific CD4+ TRM in these grafts provided enhanced protection against secondary infection. These cells were insufficient to mediate protection alone, instead recruiting circulating memory T cells to the site of infection in a chemokine-dependent fashion.
The Glennie et al. study allows a key commonality to be drawn between TRM subsets, as CD8+ TRM in the skin and mucosa have been shown to provide immune protection in a similar fashion, involving the enhanced recruitment of immune cells into the infected tissue. Diseases caused by Leishmania represent a significant global health problem, and there is no available vaccine against this parasite. This study has major implications for the design of an effective Leishmania vaccine, highlighting that control of this pathogen depends on both resident and circulating memory T cell populations. A major advantage of a vaccine designed to generate TRM is that these cells might also directly provide rapid protection at the site of infection, which would allow for immune control before pathogen dissemination and spread.