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

Biol Blood Marrow Transplant. 2019 Apr;25(4):648-655. doi: 10.1016/j.bbmt.2018.12.066. Epub 2018 Dec 19.

Abstract

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.

Keywords: GVHD; Immune reconstitution; Interleukin-7; Lymphocytes; Lymphopenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / metabolism*
  • Graft vs Host Disease / metabolism*
  • Hematopoietic Stem Cell Transplantation / methods*
  • Humans
  • Interleukin-7 / metabolism*
  • Mice
  • Transplantation Conditioning / methods*
  • Transplantation, Homologous / methods*

Substances

  • Interleukin-7