TCF-1 acts as a positive regulator in alloactivated T cells, and TCF-1 deficiency reduces GVHD yet maintains GVT responses

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for hematological malignancies. Mature donor T cells in this graft help kill residual malignant cells (graft-versus-tumor or GVT effect). However, donor T cells also damage healthy host tissue, causing graft-versus-host disease (GVHD) in about 30–70% of allo-HSCT patients. These alloactivated T cells proliferate, migrate to target organs (liver, skin, and small intestine), and produce cytokines during GVHD. Our work focuses on modulating T cell signaling to separate GVHD from GVT, as GVHD is the main clinical barrier to widespread use of allo-HSCT. T Cell Factor-1 (TCF-1) is critical for T cell development and activation, but its role in alloactivated and mature T cells is unclear. Using a mouse model of MHC-mismatched allo-HSCT leading to GVHD, we examined the role of TCF-1 in this context. Loss of TCF-1 specifically in T cells led to reduced severity and persistence of GVHD, and reduced host tissue damage from both CD4 and CD8 T cells, yet maintained GVT effects. Cytokine production, proliferation, and survival of donor T cells, as well as donor T cell phenotype, were all affected by loss of TCF-1. Therefore, TCF-1 controls mature T cell phenotype and function during allo-HSCT, and is indispensable for GVHD damage. TCF-1 is dispensable for GVT effects, because loss of this factor does not disrupt antitumor immunity. Thus, loss of TCF-1 separates detrimental GVHD damage from beneficial GVT effects. This work will help to improve outcomes for allo-HSCT patients, who have poor survival due to GVHD and increased risk of deadly infections. This research also enhances our basic understanding of how alloactivated mature T cells are regulated during allo-HSCT.