Stromal-Derived Factor-1α and Interleukin-7 Treatment Improves Homeostatic Proliferation of Naïve CD4+ T Cells after Allogeneic Stem Cell Transplantation

• CD4+ T cell reconstitution is impaired after allogeneic stem cell transplantation.
• Low interleukin-7 and dendritic cell counts constrain CD4 homeostatic proliferation during graft-versus-host disease.
• Stromal-derived factor-1α production is diminished during graft-versus-host disease.
• Stromal-derived factor-1α and interleukin-7 can improve CD4 homeostatic proliferation during graft-versus-host disease.

Graft-versus-host disease (GVHD) impairs immune reconstitution after allogeneic stem cell transplantation (allo-SCT) and effective therapies aimed at restoring T cell counts in GVHD patients have yet to be developed. During GVHD, CD4+ T cell reconstitution is particularly affected and current models hold that GVHD insult to the peripheral lymphoid niche is responsible for this effect. Here, we show that naïve CD4+ T cell homeostatic proliferation (HP) is lost during GVHD because of low systemic IL-7 and impaired dendritic cell (DC) regeneration. We assessed factors involved in DC differentiation and found that although fms-like tyrosine kinase 3 ligand (Flt3-L) levels were normal, stromal-derived factor-1α (SDF-1α) was diminished in the blood of GVHD mice. Unlike Flt3-L treatment, the administration of SDF-1α specifically increased CD8α+ DC numbers and did not worsen GVHD. Importantly, CD4+ T cell HP was enhanced only when IL-7 and SDF-1α or Flt3L were coadministered, confirming the crucial role of DCs and IL-7 in restoring CD4+ T cell regeneration during GVHD. Altogether, our results indicate that CD8α+ DCs are part of the peripheral niche that controls CD4+ T cell HP and that their depletion, combined with low systemic IL-7, explains how GVHD constrains naïve CD4+ T cell reconstitution after allo-SCT.