Room: F

317.2 Immune Profiling of Migrating and Graft-associated γδ T cells after Human Intestinal Transplantation Reveals Unique Innate and Adaptive Features

Jianing Fu, United States

Assistant Professor
Medicine
Columbia University

Abstract

Immune profiling of migrating and graft-associated γδ T cells after human intestinal transplantation reveals unique innate and adaptive features

Jianing Fu1,2, Zhou Fang1, Alaka Gorur1, Wenyu Jiao1, Zicheng Wang3, Elizabeth Waffarn1, Katherine D. Long1, Rebecca Jones1, Kortney Rogers1, Constanza Bay Muntnich1, Yufeng Shen3, Prakash Satwani4, Joshua Weiner1,5, Mercedes Martinez4, Tomoaki Kato5, Megan Sykes1,2,5,6.

1Columbia Center for Translational Immunology, Columbia University, New York, NY, United States; 2Department of Medicine, Columbia University, New York, NY, United States; 3Department of Systems Biology, Columbia University, New York, NY, United States; 4Department of Pediatrics, Columbia University, New York, NY, United States; 5Department of Surgery, Columbia University, New York, NY, United States; 6Department of Microbiology & Immunology, Columbia University, New York, NY, United States

Introduction: Innate- and adaptive-like features of human γδ T cells are associated with different T cell receptor (TCR) repertoires, defined as Vγ9+δ2+ and non-Vγ9δ2, respectively. Immune repertoires can be shaped by tissue compartmentalization, age and history of antigen exposure. Despite comprising a significant portion of lymphocytes residing in many organs, including gut, the role of γδ T cells in transplantation outcomes is unclear.

Methods: Serial biopsies from intestinal transplantation (ITx) recipients allow us to investigate the turnover dynamics of intragraft γδ T cells in the presence and absence of rejection, providing a unique opportunity to study the fundamental biology of human γδ T cells. Clonal tracking of γδ T cells in intestinal grafts, peripheral blood and bone marrow (BM) at both pre- and post-Tx time points provides a deeper understanding of their tissue origin, migration pattern and phenotypic maturation. Integrated iRepertoire (γδ T cell primer sets) and 10x Genomics (5’cDNA library) platforms were applied to relate functional gene profiles within individual γδ T cell clonotypes.

Results: We previously demonstrated that donor T cell macrochimerism (peak level ≥4% in blood) is associated with less rejection. We now show that high levels (>10%) of γδ T cell blood chimerism were only observed in patients with macrochimerism. Remarkably, donor γδ T cells were detected in recipient BM 105–357 days post-Tx. Single-cell profiling of BM-infiltrating donor γδ T cells revealed both Vδ1- and Vδ2-dominant clonotypes with cytotoxic effector phenotypes that might contribute to graft-vs-host responses. In one multivisceral Tx patient, the top dominant donor γδ TCR clone (Vγ8Vδ1) detectable during the peak T cell chimerism in blood (8–20 days post-Tx) was also predominantly present in the recipient BM 126 days post-Tx, with clear cytotoxic profiles (GZMB/PRF1/GNLY) but reduced proliferation (MKI67) and BM-homing (CXCR4) features. BM-infiltrating donor Vδ2 clonotypes tended to be more “public” and were shared by three pediatric patient post-Tx BM specimens and pre-Tx repertoires across pediatric donors and tissues. Many of these Vδ2 clones are Vγ9δ2 with zero N-additions that likely originate from fetal liver and cord blood. However, these Vδ2-dominant clones were not present in adult lymphoid tissues, gut or BM, suggesting an age-related distribution and migration pattern. In contrast to αβ T cells, the turnover dynamics of γδ T cells in the graft showed a stronger association with donor age than with the status of macrochimerism. Graft-repopulating recipient γδ T cells showed activated effector phenotypes early post-Tx and gradually developed into cytotoxic resident-memory T cells with “private” Vδ1 clonotypes.

Conclusions: γδ T cells have the potential to modulate immune responses to influence T cell chimerism locally and systemically. They may participate in host defense and graft rejection after ITx.



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