GM-CSF induces differentiation of bone marrow precursors into tolerogenic CD8a- dendritic cells (50.32)

Abstract

Abstract Experimental autoimmune thyroiditis, a murine model of Hashimoto's thyroiditis is characterized by the infiltration of the thyroid by self-reactive CD4+ T cells. Our earlier studies have shown that GM-CSF treatment of experimental animals can suppress ongoing thyroiditis through the induction of tolerogenic CD8a- dendritic cells (DCs) expressing low levels of pro-inflammatory cytokines. Antigen presentation by these tolerogenic CD8a- DCs resulted in an expansion of IL-10 secreting CD4+Foxp3+ regulatory T-cells (T-regs) which suppressed the effector T-cell function. To understand the underlying mechanism we studied the effect of GM-CSF on matured splenic DCs as well as on bone marrow (BM) DC precursors in vitro. In spite of increased surface expression of programmed death ligand 2 (PDL-2), a negative regulator of T-cell activation, and increased indole-deoxygenase (IDO) secretion, splenic DCs exposed to GM-CSF induced only a modest increase in Foxp3 expression in T-cells. In contrast, BM cells when cultured in the presence of GM-CSF gave rise to a population of CD11c+CD11bhigh DCs with lower levels of expression of pro-inflammatory cytokines IL-12 and IL-6 which induced Foxp3 expression in a very high percentage of T-cells in a contact dependent manner. Our studies strongly suggest that the tolerogenic effect of GM-CSF is mediated by a special class of CD8a- DCs that differentiate from BM precursors. NIH 1RO1AI058190