The human tissue-resident CCR5 ⁺ T cell compartment maintains protective and functional properties during inflammation

Abstract

CCR5 is thought to play a central role in orchestrating migration of cells in response to inflammation. CCR5 antagonists can reduce inflammatory disease processes, which has led to an increased interest in using CCR5 antagonists in a wide range of inflammation-driven diseases. Paradoxically, these antagonists appear to function without negatively affecting host immunity at barrier sites. We reasoned that the resolution to this paradox may lie in the CCR5+ T cell populations that permanently reside in tissues. We used a single-cell analysis approach to examine the human CCR5+ T cell compartment in the blood, healthy, and inflamed mucosal tissues to resolve these seemingly contradictory observations. We found that 65% of the CD4 tissue-resident memory T (TRM) cell compartment expressed CCR5. These CCR5+ TRM cells were enriched in and near the epithelial layer and not only limited to TH1-type cells but also contained a large TH17-producing and a stable regulatory T cell population. The CCR5+ TRM compartment was stably maintained even in inflamed tissues including the preservation of TH17 and regulatory T cell populations. Further, using tissues from the CHARM-03 clinical trial, we found that CCR5+ TRM are preserved in human mucosal tissue during treatment with the CCR5 antagonist Maraviroc. Our data suggest that the human CCR5+ TRM compartment is functionally and spatially equipped to maintain barrier immunity even in the absence of CCR5-mediated, de novo T cell recruitment from the periphery.

Coronavirus infections: Epidemiological, clinical and immunological features and hypotheses

“…Only highly specialized laboratories are able to conduct experiments to investigate immune responses against HLA class-I and class-IIrestricted viral epitopes mediated by CD8+ and CD4+ T lymphocytes, respectively, to confirm the conjecture of a cellular (rather than humoral) immunity against SARS-CoV-2. Moreover, the T lymphocytes responsible for clinically relevant antiviral immune responses have high chances to be locally present in, or close to, respiratory epithelia but have comparatively low chances to be detectable in peripheral blood [57][58][59]. It is well possible that the exclusive detection of humoral immunity (antibodies against SARS-CoV-2) leads to an underestimation of the anti-SARS-CoV-2 immune responses.…”

Beyond HIV infection: Neglected and varied impacts of CCR5 and CCR5Δ32 on viral diseases

“…CCR5 is also expressed by tissue-resident memory T cells. These CCR5 + cells support barrier immunity (Davis et al, 2019).…”

Human Tissue-Resident Memory T Cells in the Maternal–Fetal Interface. Lost Soldiers or Special Forces?

“…Within the T cell compartment, a near 1:1 CD4/CD8 T cell ratio was observed in healthy endometrial biopsies at the secretory phase of the menstrual cycle [54][55][56]. This distribution substantially differs from that of blood (in which CD4 T cells are more frequent) and mirrors that of other barrier tissues that are largely populated by Trm cells, including the endocervix, ectocervix, and vagina [45,57,58]. Indeed, endometrial memory T cells (defined by CD45RO positivity) expressed CD69 (and to a lesser extent, CD8 T cells coexpressed CD103) [54] suggesting that Trm cells are present at the window of implantation.…”

“…While most Trm cells have a Tem-like phenotype, those with Temra phenotypes can also contribute to tissue residence [ 58 ], yet do not express CD45RO, potentially explaining the reported CD69 expression in CD45RO − endometrial T cells [ 54 ]. In line with bona fide tissue residence, CD69 + memory T cells isolated from the endometrium express the proteins PD-1 [ 54 ] or CCR5 [ 55 ] and transcripts for CD49a [ 59 ], mirroring phenotypic and transcriptional signatures broadly shared by human Trm cells across mucosal and lymphoid tissues [ 45 , 49 , 57 ]. While CCR5 expression has long been associated with a Th1 phenotype [ 60 ], a recent study demonstrated that CCR5 + CD4 T cells in healthy and inflamed human barrier tissue are actually potent IL-17 producers [ 45 ].…”

“…Trm cells have been characterized across a range of human tissues including skin, lung, gut, oral mucosa, and the female reproductive tract [ 35 , 42 , 43 , 44 , 45 ]. Mouse model studies have shown that memory T cells can traffic to tissues regardless of the presence of antigen in the tissue [ 46 , 47 ], but also suggest that in situ infection and antigen availability are critical factors for effective Trm retention [ 48 ].…”