A New Lens into the Tissue-Specific Landscape of the T Cell Repertoire in Human Graft-Versus-Host-Disease
Thursday, June 23, 2022
3:15 PM – 3:30 PM PT
Location: Salons 1/2
Authors: Susan DeWolf, MD (Presenting Author) - Memorial Sloan Kettering Cancer Center; Katherine Nichols, n/a (Co-Author) - Memorial Sloan Kettering Cancer Center; Yuval Elhanati, Ph.D. (Co-Author) - Memorial Sloan Kettering Cancer Center; Chi Nguyen, n/a (Co-Author) - Memorial Sloan Kettering Cancer Center; Nicholas Water, Ph.D. (Co-Author) - Memorial Sloan Kettering Cancer Center; Natasia Rodriquez, n/a (Co-Author) - Memorial Sloan Kettering Cancer Center; Paul Giardina, n/a (Co-Author) - Memorial Sloan Kettering Cancer Center; John Slingerland, B.S. (Co-Author) - Memorial Sloan Kettering Cancer Center; Hana Andrlova, MD (Co-Author) - Memorial Sloan Kettering Cancer Center; Rajya Kappagantula, n/a (Co-Author) - Memorial Sloan Kettering Cancer Center; Yanyun Li, n/a (Co-Author) - Memorial Sloan Kettering Cancer Center; Priscilla Baez, n/a (Co-Author) - Memorial Sloan Kettering Cancer Center; Rajmohan Murali, MD (Co-Author) - Memorial Sloan Kettering Cancer Center; Akimasa Hayashi, MD, Ph.D. (Co-Author) - Kyorin University; Nicole Lee, n/a (Co-Author) - Memorial Sloan Kettering Cancer Center; Anqi Dai, M.S. (Co-Author) - Memorial Sloan Kettering Cancer Center; Anastasia Kousa, Ph.D. (Co-Author) - Memorial Sloan Kettering Cancer Center; Amanda Blouin, MD, Ph.D. (Co-Author) - Memorial Sloan Kettering Cancer Center; Doris Ponce, MD (Co-Author) - Memorial Sloan Kettering Cancer Center; Heather Landau, MD (Co-Author) - Memorial Sloan Kettering Cancer Center; Ioannis Politikos, MD (Co-Author) - Memorial Sloan Kettering Cancer Center; Roni Tamari, MD (Co-Author) - Memorial Sloan Kettering Cancer Center; Alan Hanash, MD, Ph.D. (Co-Author) - Memorial Sloan Kettering Cancer Center; Robert Jenq, MD (Co-Author) - University of Texas MD Anderson Cancer Center; Sergio Giralt, MD (Co-Author) - Memorial Sloan Kettering Cancer Center; Kate Markey, MD, Ph.D. (Co-Author) - Fred Hutchinson Cancer Research Center; Yanming Zhang, MD (Co-Author) - Memorial Sloan Kettering Cancer Center; Miguel-Angel Perales, MD (Co-Author) - Memorial Sloan Kettering Cancer Center; Nicholas Socci, Ph.D. (Co-Author) - Memorial Sloan Kettering Cancer Center; Benjamin Greenbaum, Ph.D. (Co-Author) - Memorial Sloan Kettering Cancer Center; Christine Iacobuzio-Donahue, MD, Ph.D. (Co-Author) - Memorial Sloan Kettering Cancer Center; Travis Hollmann, MD, Ph.D. (Co-Author) - Memorial Sloan Kettering Cancer Center; Marcel van den Brink, MD, Ph.D. (Co-Author) - Memorial Sloan Kettering Cancer Center; Jonathan Peled, MD, Ph.D. (Co-Author) - Memorial Sloan Kettering Cancer Center
Investigating T cell immunity in tissues is critical for understanding immune responses at the site of pathology, such as in graft-versus-host-disease (GVHD), an adverse sequela of transplantation. This often-lethal complication arises from alloreactive T cells leading to inflammation within tissues, such as the skin or gastrointestinal (GI) tract. We profiled the TCR repertoire in GVHD tissues in mice after receiving a major MHC-disparate allograft (6-8 tissues/mouse, 129 total tissues), revealing the greatest clone sharing by similarity of the anatomic region, such as across GI tract sections. We found a significant frequency increase in dominant clones from day 7 to 14 post-transplant, consistent with expansion of TCRs within tissues. To investigate human T cells in tissues directly, we studied a unique patient cohort via prospectively collected autopsy material: seven patients with hematologic cancers who underwent curative treatment with bone marrow transplantation whose post-transplant course was complicated by refractory GVHD and three comparator cancer patients who did not undergo transplantation. We profiled multiple sites per individual (5-18 samples/patient, 98 total samples) via TCR sequencing and found greater repertoire sharing across anatomically similar regions, regardless of transplant history, despite heterogeneity in degree of overlap. A computational motif-based clustering approach found evidence of potentially shared antigen-specific TCR motifs clustering by tissue across patients. Furthermore, in mice and humans, the blood and/or spleen repertoire did not fully capture the TCRs in tissues. Taken together, our work provides new insights into the site-specificity of the T cell repertoire, highlighting the importance of analyzing tissue-resident T cells.