Emerging Concepts of Tissue-resident Memory T Cells in Transplantation

Abstract

In this review, we summarize and discuss recent advances in understanding the characteristics of tissue-resident memory T cells (TRMs) in the context of solid organ transplantation (SOT). We first introduce the traditionally understood noncirculating features of TRMs and the key phenotypic markers that define this population, then provide a detailed discussion of emerging concepts on the recirculation and plasticity of TRM in mice and humans. We comment on the potential heterogeneity of transient, temporary resident, and permanent resident T cells and potential interchangeable phenotypes between TRM and effector T cells in nonlymphoid tissues. We review the literature on the distribution of TRM in human nonlymphoid organs and association of clinical outcomes in different types of SOT, including intestine, lung, liver, kidney, and heart. We focus on both tissue-specific and organ-shared features of donor- and recipient-derived TRMs after transplantation whenever applicable. Studies with comprehensive sample collection, including longitudinal and cross-sectional controls, and applied advanced techniques such as multicolor flow cytometry to distinguish donor and recipient TRMs, bulk, and single-cell T-cell receptor sequencing to track clonotypes and define transcriptome profiles, and functional readouts to define alloreactivity and proinflammatory/anti-inflammatory activities are emphasized. We also discuss important findings on the tissue-resident features of regulatory αβ T cells and unconventional γδ T cells after transplantation. Understanding of TRM in SOT is a rapidly growing field that urges future studies to address unresolved questions regarding their heterogeneity, plasticity, longevity, alloreactivity, and roles in rejection and tolerance.

The Entangled World of Memory T Cells and Implications in Transplantation

“…36 Recipient-derived T RM that become established in the graft, whether antigen-specific or polyclonal, are highly functional and have the capability to maintain cellular-mediated rejection within the graft and are persistently exposed to alloantigen, without acquiring phenotypic or functional characteristics of T-cell exhaustion. 19 Fu and Sykes 37 review the role of T RM in solid organ transplantation and rejection further. Additional work has also revealed significant roles of tissue-resident innate lymphoid cells that further contribute to rejection within the peripheral tissue, which was recently reviewed by Charmetant et al 38…”

Novel approaches for long-term lung transplant survival

“…More recently, the existence of recirculating TRMs has been identified, implying that TRMs may be capable of participating in systemic recall responses ( 215 – 217 ). Furthermore, the observation that graft-infiltrating recipient T-cells gradually acquire TRM markers suggests that these cells may actually represent repopulation of donor lung tissue by circulating effector memory T-cells that then acquire TRM phenotypes or by recirculating ex-TRMs ( 218 ). The ability of TRM cells to influence the immune environment within lung allografts through rapid in-situ and potentially also systemic immune responses represents yet another avenue for targeted interventions to prevent allograft injury and rejection.…”

Tissue-resident memory T cells in chronic liver diseases: Phenotype, development and function

“…Specifically, long-term persistence of lung donor-derived T RM cell is associated with reduced incidence of clinical events that precipitate allograft injury, including primary graft dysfunction (PGD) and acute cellular rejection (ACR) ( 149 ). However, the association of liver donor-derived T RM cells with the incidence of clinical events remains to be further elucidated ( 150 ). In liver allograft tissues, approximately 2-6% of CD8 + T cells had a donor-derived T RM phenotype at 11 years post-transplantation ( 18 ), well demonstrating the longevity of human liver T RM cells.…”