IL-23 induces apoptosis of self-reactive thymocytes in thymic negative selection by an Rorc dependent mechanism (64.19)

Abstract

Listen

Translate article

Abstract Thymocyte apoptosis can occur by over-induction of a specific transcription factor, RORγt (or its gene, Rorc); however, the role of RORγt in thymocyte selections and the upstream signal that drives the expression of Rorc are largely unknown. We have observed that interleukin-23 (IL-23), a cytokine which has been implicated as a key regulator of Rorc, was expressed by thymic dendritic cells. To determine if the IL-23-RORγt signaling axis is involved in thymocyte selections, we have determined the expression of Il23r and Rorc in thymocytes from the male antigen-specific Db/H-Y T-cell receptor (TCR) transgenic (Tg) and the MOG35-55 antigen-specific 2D2 TCR Tg mice. Specific antigen activation induced Il23r expression on CD4+CD8+ double positive (DP) thymocytes and then upregulated the expression of Rorc with IL-23 stimulation, leading to dramatic induction of DP thymocyte apoptosis in vitro in TCR Tg+ mice. In vivo over-expression of IL-23 in B6 mice by adenovirus (AdIL-23) efficiently depleted DP thymocytes by promoting apoptosis (from 1.5% to 10%) as determined by in situ TUNEL staining. This AdIL-23 induced thymocyte apoptosis was partially blocked in Rorc+/- mice. Consistent with these, there was an increased percent of Db/H-Y Tg+ thymocytes in Il23 p19-/- mice, compared with that in p19 intact male Db/H-Y Tg mice. Taken together, our work suggests an important role for the IL-23-RORγt axis in the induction of TCR-mediated apoptosis and negative selection in thymocytes.