The Restorative Effect of Flt3-Ligand and IL-7 On CD4+ T Cell Homeostatic Proliferation During Graft-Versus-Host Disease

Allogeneic hematopoietic stem cell transplantation (SCT) is the best treatment for numerous types of hematological malignancies. However, graft-versus-host disease (GVHD) is the major cause of morbidity and mortality and its effect on T cell regeneration greatly exacerbates the immunodeficiency normally associated with this treatment. As a result, patients with GVHD are profoundly lymphopenic and T cell reconstitution typically takes several months or years. 

We previously reported that IL7Ra^-/- mice have a peripheral lymphoid niche that is highly permissive for homeostatic proliferation (HP) of CD4⁺ T cells. Given that CD4⁺ T cells regeneration is impaired during GVHD, we hypothesized that using IL7Ra^-/- bone marrow (BM) might improve their recovery in GVHD hosts. To study the impact of GVHD on the peripheral niche regulating CD4 HP, we used the mouse model B6 into B6D2F₁. Since  IL7Ra^-/- DCs support efficiently HP of naïve CD4⁺ T cells during lymphopenia, we used BM stem cells from B6IL7Ra^-/- mice and induced GVHD by adding 1x10⁶  B6 T cells.  Finally, to understand the impact of GVHD on HP, we transferred CFSE labelled anti-HY CD4⁺ T cells (Marilyn) into GVHD hosts and measured their homeostatic proliferation 7 days later.

In non GVHD hosts, Marilyn T cells underwent robust HP while they completely failed in GVHD hosts. Absence of HP during GVHD was associated with a severe depletion of all DC subsets, including myeloid, lymphoid and pDCs. Low number of DCs during GVHD was in part due to their elimination by GVHD T cells but most importantly to a myelosuppression affecting DC production from BM progenitor cells.  Interestingly, treatment of GVHD mice with FLT3 ligand (FL) significantly increased the number of DCs, yet it was insufficient for restoring CD4 HP. Given that stromal cells and IL7 mRNA levels were also diminished in GVHD hosts, we provided both FL and IL-7 to GVHD mice and significantly restored HP of Marilyn CD4⁺ T cells in this setting.

Thus far, our data support a model wherein loss of CD4 HP during GVHD relates to lower numbers of DC and diminished systemic IL7.