The influence of CD4 T-cell subsets on control of CD4 T-cell-mediated graft-versus-host disease.

In this study, we tested the effect of different T-cell subpopulations on antigen driven effector cell expansion in lymphopenic hosts, making use of an experimental model of graft-versus-host disease (GVHD). Fluorescence-activated cell sorted (FACS) naïve CD4 T cells from C57BL/6 mice, transferred into lymphopenic F1 (C57BL/6 x BALB/c) Rag-deficient hosts, proliferated extensively and migrated systemically causing acute GVHD within 4 weeks after transfer. Adoptive hosts of CD4 memory T cells on the other hand developed milder symptoms of GVHD with later onset. T-cell expansion and migration to peripheral sites as well as development of GVHD were prevented when naïve T cells were transferred together with CD4(+) CD25(+) T cells, but co-transfer of memory T cells with naïve T cells could not prevent GVHD, although its onset was delayed. OX40, a costimulatory marker that is upregulated at an early time point after T-cell activation and enhances T-cell proliferation, cytokine secretion and survival, was strongly upregulated during GVH responses. Naïve T cells deficient in OX40 expression caused markedly reduced GVH in onset and severity despite some level of expansion in the adoptive host, suggesting an important role of this molecule in the immune pathology of GVHD.