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458 TCF-1 is Required By CD8+ T Cells for the Maintenance of Alloimmune Responses in Graft-Vs-Host Disease

Program: Oral and Poster Abstracts
Type: Oral
Session: 701. Experimental Transplantation: Basic and Translational: T Cells in GVHD, Thymus Regeneration, and Immune Reconstitution
Hematology Disease Topics & Pathways:
Research, Fundamental Science, GVHD, Immune Disorders, Diseases
Sunday, December 10, 2023: 9:45 AM

Kevin Quann, MD, PhD1, Faruk Sacirbegovic, PhD2*, Sarah Rosenberger, MS1*, Emily McFerran, BS1*, Kentin Codispot, BS3* and Warren Shlomchik, MD1*

1Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA
2Department of Surgery, University of Pittsburgh, Pittsburgh, PA
3Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh

Graft-vs-host disease (GVHD) is a common complication of allogeneic stem cell transplant (alloSCT) wherein donor T cells target alloantigens on recipient tissues. It is unclear how alloimmune responses are maintained in GVHD despite abundant antigen, which causes T cell anergy, deletion and exhaustion. Previously, we identified alloreactive TCF-1high T cells arising post-transplant that resemble exhausted progenitors (TEXP) capable of propagating immune responses in other chronic antigen models. Here, we sought to further characterize these cells in the B6→129 MHC-matched GVHD mouse model, in which 129 recipients express the immunodominant H-2Kb-restricted minor histocompatibility antigen (miHA) H60. At day +7 post-transplant, alloreactive CD8+ cells specific to H60 (as determined by MHC-I-tetramer staining; TetH60+) were nearly uniformly PD-1hiToxhi whereas TetH60- cells displayed a bimodal distribution into discrete PD-1hiToxhi and PD-1loToxlo populations, indicative of more diverse antigen experiences. Among these both TetH60+ and TetH60- cells were TCF-1hi cells. TCF-1hi TetH60+ cells were uniformly CD39loToxhiPD-1hi, which is a canonical TEXP phenotype. In contrast, among activated TetH60- cells there were TCF-1hi cells that were CD39loToxhiPD-1hi and ToxloPD-1lo. At later times in spleen and lymph node, and in GVHD target tissues, these populations of TCF-1+ TetH60+ and TetH60- were found. To test if these CD39loTCF-1hi TEXP had proliferative advantages in GVHD, we sorted congenic TCF-1hiCD39lo and TCF-1loCD39hi CD8+ cells from recipient spleens 14-days post-transplant and adoptively transferred them in competition in a 1:1 ratio (of TetH60+ cells) into newly transplanted recipients. Among TetH60+ cells in all tissues at day 14 post-transfer, TCF-1hiCD39lo-sorted progeny greatly outperformed TCF-1loCD39hi-sorted progeny. In line with their role as a source of GVHD effectors, progeny of TCF-1hiCD39lo cells were mostly TCF-1loCD39hi; however, a fraction remained TCF-1hi consistent with their being able to undergo self-renewal. Conversely, we observed few if any TCF-1+ progeny of CD39hi cells. We next tested whether TCF-1 was an important mediator of T cell fitness or whether it was only a marker for functionality. To do so we competed congenic wild-type (WT) and Tcf7p45-/- (p45-/-) donor CD8 cells, which lack the N-terminal β-catenin binding domain of TCF-1, in allogeneic (129) and syngeneic (B6) recipients. Strikingly, p45-/- CD8 cells were greatly outcompeted by WT CD8 cells in 129 recipients in all tissues and at all times post-transplant, among both TetH60+ and TetH60- cells. In contrast, in B6 recipients, WT and p45-/- cells remained evenly matched, suggesting that full-length TCF-1 isoforms are dispensable for lymphopenia-induced T cell expansion. Further, p45-/- cells were also not disadvantaged when adoptively transferred into B6 mice and acutely challenged with H60 antigen by vaccination. Together these data suggest a model wherein TCF-1hi progenitor like T cells are seeded in GVHD target organs where they may serve as a key local source for GVHD effectors, and moreover, full-length TCF-1 is itself critical for alloreactive T cell fitness in GVH responses.

Disclosures: Shlomchik: BlueSphere Bio: Current Employment, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Orca Bio: Consultancy, Current holder of stock options in a privately-held company.

*signifies non-member of ASH