Staged development of long-lived T-cell receptor αβ T H 17 resident memory T-cell population to Candida albicans after skin infection

Abstract

These studies demonstrate that C albicans infection of skin preferentially generates CD4 IL-17-producing T cells, which mediate durable protective immunity.

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…Interestingly, C. albicans infection induces a distinct population of IL-17 producing and largely sessile CD69 + CD4 + T RM cells in the superficial layer of the dermis providing C. albicans-specific protection. 174 These IL-17 + CD4 + T RM cells are often co-localized with CD11c + dendritic cells months after the clearance of the infection, suggesting a role for residual antigen or inflammatory cues for the retention of skin CD4 + T RM population. Consistent with previous findings that many dermis CD4 + T cells are rapidly exchanging with the blood, a substantial subset of circulating CD4 + T cells is present in the deeper layer of the dermis.…”

Circulating CD4+ memory T cells give rise to a CD69+ resident memory T cell population in non-inflamed human skin

“…1d). These two distinct memory subsets, a resident memory-like CD4 + CD69 + and a CD69 -CD62L + migratory population, replicate two major sets of memory T cells in healthy human skin (Park et al 2018). Taken together, these data show that circulating CD4 + memory T cells have the ability to up-regulate markers of tissue-residency upon entry into non-inflamed/non-infected human skin.…”

“…TRM are defined by the expression of CD69 and/or CD103, both of which contribute to tissue retention (Mackay et al 2015;Mackay et al 2013). CD4 + CD69 + TRM are generated in response to microbes such as C.albicans and provide protective immunity upon secondary infection in mouse skin, and a similar CD4 + CD69 + T cell population that produced IL17 in response to heat killed C.albicans ex vivo was found in human skin (Park et al 2018). By contrast, a population of fast migrating CD69 -CD4 + memory T cells entered murine dermis even 45 days after C.albcians infection when the infection was already resolved, hence they were likely not recruited in response to antigen.…”

“…Re-entry into the tissue to regain residency at distant skin sites would facilitate dispersion of protective immunity across large barrier organs such as the skin. The presence of a migratory memory T cell population in previously infected skin (Park et al 2018) implies the existence of circulating memory T cells that can enter non-infected skin in steady state. So far it remains to be elucidated if human circulating CD4 + memory T cells can give rise to resident memory T cells in human skin in absence of acute infection.…”

A novel humanized mouse model to study the function of human cutaneous memory T cells in vivo in human skin

“…As such, healthy human skin contains a large number of CD45RO+ memory T cells 1,2 that support tissue homeostasis and ensure adequate response to pathogens 3-5. A population of resident memory T (TRM) cells is found within most tissues where it remains long-term and provides protective immunity after TRM differentiation in response to primary infection 6,7. Additionally, TRM may have a protective function in organ transplantation 8 and support immuno-surveillance against melanoma 9. Cutaneous memory T cells have also been implicated in several diseases, such as cutaneous T cell lymphoma specifically mycosis fungoides 10,11. Generation and maintenance of memory T cells have been extensively studied using murine models 12,13,[13][14][15][16], and significant advances in understanding the role of the skin microenvironment on T cell function and memory development in murine skin have been made 15,17,18. Since T cell responses are strongly influenced by the surrounding tissue 19,20, and T cells show site-specific functional and metabolic properties 18,21, it is crucial to study cutaneous immunity within its physiological compartment in vivo. However, direct translation from the murine cutaneous immune system is complicated by fundamental structural differences, as well as a lack of direct correspondence between human and murine immune cell populations 4,22-24. Due to technical and ethical limitations, studies of human memory T cell generation have mostly been restricted to ex vivo analyses and in vitro experiments, and the specific contribution of keratinocyte-and fibroblast-derived signals to cutaneous immunity in human skin remains poorly understood.…”