Graft-versus-host disease prophylaxis shapes T cell biology and immune reconstitution after hematopoietic cell transplant.
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DeWolf Susan, Siegel Steven J, Schmalz Joseph, Saber Wael, Albanese Alexandre, Dong Jiayi, Martens Michael J, Logan Brent, Iovino Lorenzo, Ingersoll-Ohmdahl Kayleigh, Winn Nicholas, Chen Edward, Kaminski James, Neuberg Donna, Hebert Kyle, Keskula Paula, Zavistaski Jillian, Steinberg Lea, Schichter Isabella, Katsamakis Zoe, Cagnin Lorenzo, Hernandez Vanessa, Warren Makya, Applegate Kristy, Bar Merav, Chhabra Saurabh, Choi Sung Won, Clark William, Das Suman, Jenq Robert, Jones Richard J, Levine John E, Murthy Hemant, Rashidi Armin, Riches Marcie, Sandhu Karamjeet, Sung Anthony D, Larkin Karilyn, Al Malki Monzr M, Gooptu Mahasweta, Elmariah Hany, Alousi Amin, Runaas Lyndsey, Shaffer Brian, Rezvani Andrew, El Jurdi Najla, Loren Alison W, Scheffey Danielle, Sanders Catherine, Hamadani Mehdi, Dudakov Jarrod A, Bien Stephanie, Robins Harlan, Horowitz Mary, Bolaños-Meade Javier, Holtan Shernan, Bhatt Ami S, Perales Miguel-Angel, Kean Leslie S
Аннотация
Successful 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.