IL-7 Is the Limiting Homeostatic Factor that Constrains Homeostatic Proliferation of CD8+ T Cells after Allogeneic Stem Cell Transplantation and Graft-versus-Host Disease

Immune reconstitution after allogeneic hematopoietic stem cell transplantation relies primarily on homeostatic proliferation (HP) of mature T lymphocytes, but this process is typically impaired during graft-versus-host disease (GVHD). We previously showed that low IL-7 levels combined with lack of dendritic cell (DC) regeneration constrain CD4⁺ T cell HP during GVHD. However, it is not clear whether these alterations to the peripheral CD4⁺ T cell niche also contribute to impair CD8⁺ T cell regeneration during GVHD. We found that IL-7 therapy was sufficient for restoring CD8⁺ T cell HP in GVHD hosts while forcing DC regeneration with Flt3-L had only a modest effect on CD8⁺ T cell HP in IL-7 treated mice. Using bone marrow chimeras, we showed that HP of naïve CD8⁺ T cells is primarily regulated by MHC class I on radio-resistant stromal cells, yet optimal recovery of CD8⁺ T cell counts still requires expression of MHC class I on both radio-resistant and radio-sensitive hematopoietic cells. Thus, IL-7 level is the primary limiting factor that constrains naïve CD8⁺ T cell HP during GVHD, and accessibility of MHC class I on stromal cells explains how IL-7 therapy, as a single agent, can induce robust CD8 ⁺ T cell HP in the absence of DCs.