Emerging Concepts of Tissue-resident Memory T Cells in Transplantation

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.