Skin-resident CD4+ T cells protect against Leishmania major by recruiting and activating inflammatory monocytes

Abstract

Tissue-resident memory T cells are required for establishing protective immunity against a variety of different pathogens, although the mechanisms mediating protection by CD4+ resident memory T cells are still being defined. In this study we addressed this issue with a population of protective skin-resident, IFNγ-producing CD4+ memory T cells generated following Leishmania major infection. We previously found that resident memory T cells recruit circulating effector T cells to enhance immunity. Here we show that resident memory CD4+ T cells mediate the delayed-hypersensitivity response observed in immune mice and provide protection without circulating T cells. This protection occurs rapidly after challenge, and requires the recruitment and activation of inflammatory monocytes, which limit parasites by production of both reactive oxygen species and nitric oxide. Overall, these data highlight a novel role for tissue-resident memory cells in recruiting and activating inflammatory monocytes, and underscore the central role that skin-resident T cells play in immunity to cutaneous leishmaniasis.

The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

“…Trm cells can provide much more immediate protection, and various studies have demonstrated that they provide the most effective immune protection to the host 14, 15, 17, 30…”

“…Three additional key approaches are used in mice to investigate whether Trm cells are truly resident: in vivo treatment with the S1P functional antagonist, FTY720; parabiosis in which the circulatory systems of two animals are surgically connected; and fate mapping using photoconvertible cells. Treatment with FTY720 restricts the migration of circulating cells, so a stable population of Trm cells in treated mice demonstrates that these cells are neither replenished by, nor lost to, circulating populations 15, 17, 40. However, FTY720 may also inhibit egress of cells from peripheral tissues to draining lymph nodes and/or reduce cell survival 35, 41, 42, 43.…”

“…Influenza‐specific memory CD4 T‐cells in the lung drive the production of chemokines that attract innate immune cells that rapidly control viral spread 51. Similarly, IFN‐ γ production by L. major ‐specific CD4 Trm cells drives the recruitment of inflammatory monocytes to the infection site 15. These recruited monocytes produce nitric oxide and reactive oxygen species that are toxic to the parasite.…”

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…175 However, during low dose re-challenge, CD4 + T RM and T RM -recruited inflammatory monocytes are sufficient to provide immediate protection without the contribution from circulating T cells. 176 …”

Chemokines: Critical Regulators of Memory T Cell Development, Maintenance, and Function

“…However, whether tissue-resident or circulating memory T cells are the important subset was not investigated. In a murine model of Leishmania, the Scott group demonstrated that pathogen-specific CD4 + Trm recruit inflammatory monocytes to the site of local infection via regulation of CCR2 ligands (Glennie, Volk, & Scott, 2017). The recruitment of these inflammatory monocytes was necessary to mount an effective recall response.…”