Tissue-resident Lymphocytes in Solid Organ Transplantation: Innocent Passengers or the key to Organ Transplant Survival?

Abstract Short-term outcomes of solid organ transplantation have improved dramatically over the past several decades; however, long-term survival has remained static over the same time period, and chronic rejection remains a major cause of graft failure. The importance of donor, or 'passenger', lymphocytes to the induction of tolerance to allografts was recognized in the 1990s; however, their precise contribution to graft acceptance or rejection has not been elucidated. Recently, specialized populations of tissue-resident lymphocytes in nonlymphoid organs have been described. These lymphocytes include tissue-resident memory T cells (Trm), regulatory T cells (Treg), gamma-delta (γδ T cells, invariant natural killer T cells (iNKT), and innate lymphoid cells (ILC). These cells reside in commonly transplanted solid organs, including the liver, kidneys, heart and lung, however, their contribution to graft acceptance or rejection has not been examined in detail. Similarly, it is unclear whether tissue-resident cells derived from the pool of recipient-derived lymphocytes play a specific role in transplantation biology. This review summarises the evidence for the roles of tissue-resident lymphocytes in transplant immunology, focussing on the features, functions and relevance of Trm, Treg, γδ T, iNKT, and ILC cells in solid organ transplantation, with specific reference to liver, kidney, heart, and lung transplantation. Corresponding author: Amy C. Prosser BSc. Hons, School of Medicine and Pharmacology, Level 5, Harry Perkins Institute of Medical Research, 6 Verdun Street, Nedlands, Western Australia, Australia, 6009, Amy.prosser@research.uwa.edu.au Joint senior authors, Axel Kallies, PhD and Michaela Lucas, MBBS, Dr med, FRACP, FRCPA Author contributions: Amy Prosser – Writing and revision of the work. Axel Kallies – Conception, content and revision of the work. Michaela Lucas - Conception, content and revision of the work. The authors declare no conflicts of interest. Funding AK is a senior research fellow of the Sylvia and Charles Viertel Foundation. AP is supported by an Australian Government Research Training Program Scholarship. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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