Graft-versus-host disease prophylaxis shapes T cell biology and immune reconstitution after hematopoietic cell transplant
Susan DeWolf, Steven J. Siegel, Joseph Schmalz, Wael Saber, Alexandre Albanese, Jiayi Dong, Michael J. Martens, Brent Logan, Lorenzo Iovino, Kayleigh Ingersoll-Ohmdahl, Nicholas Winn, Edward Chen, James Kaminski, Donna Neuberg, Kyle Hebert, Paula Keskula, Jillian Zavistaski, Lea Steinberg, Isabella Schichter, Zoe Katsamakis, Lorenzo Cagnin, Vanessa Hernandez, Makya Warren, Kristy Applegate, Merav Bar, Saurabh Chhabra, Sung Won Choi, William Clark, Suman Das, Robert Jenq, Richard J. Jones, John E. Levine, Hemant Murthy, Armin Rashidi, Marcie Riches, Karamjeet Sandhu, Anthony D. Sung, Karilyn Larkin, Monzr M. Al Malki, Mahasweta Gooptu, Hany Elmariah, Amin Alousi, Lyndsey Runaas, Brian Shaffer, Andrew Rezvani, Najla El Jurdi, Alison W. Loren, Danielle Scheffey, Catherine Sanders, Mehdi Hamadani, Jarrod A. Dudakov, Stephanie Bien, Harlan Robins, Mary Horowitz, Javier Bolaños-Meade, Shernan Holtan, Ami S. Bhatt, Miguel-Angel Perales, Leslie S. KeanSuccessful hematopoietic cell transplant requires immunosuppression to prevent graft-versus-host disease (GVHD), a lethal, T cell–mediated complication. The phase 3 BMT CTN 1703 trial demonstrated superior GVHD-free/relapse-free survival for posttransplant cyclophosphamide (PT-Cy)–based GVHD prophylaxis versus tacrolimus/methotrexate (Tac/MTX), but the T cell biology underpinning these outcomes remains unknown. To determine this, 324 patients were coenrolled onto BMT CTN 1801 to investigate the distinct T cell immune reconstitution pathways of these regimens, including extensive evaluation of T cell receptor (TCR) repertoire, via sequencing of 2359 longitudinal samples and 180,432,350 T cells. Multimodal T cell analysis revealed that PT-Cy was associated with pan–T cell deletion followed by delayed T cell expansion from a smaller founder population compared with Tac/MTX. This created a T cell diversity bottleneck, leading to reduced TCR repertoire diversity for 2 years posttransplant. Reduced TCR diversity, more common in patients receiving PT-Cy, was linked to protection against chronic GVHD when patients were analyzed without regard to study arm. Leveraging donor- and host-specific TCR clonal analysis, we determined that PT-Cy–mediated T cell depletion also depleted pathogen-specific TCRs, rendering PT-Cy patients more likely to lack detectable graft-derived pathogen-specific TCRs early after transplant, which was associated with an increased risk of severe infection. This study reveals how distinct immunosuppression strategies uniquely remodel T cell immunity and shape divergent transplant outcomes.