Abstract
Abstract CD4+FOXP3+ regulatory T cells (Tregs) express several TNF receptor superfamily (TNFRSF) members. However, it is unclear what role these molecules play in Treg development in the thymus. We found that CD4+CD25+FOXP3- Treg progenitors and CD4+CD25+FOXP3+ thymic Tregs, but not CD4SP conventional thymocytes, express high levels of OX40, GITR, and TNFR2. Utilizing a novel Nur77-GFP Bac reporter mouse in which thymocyte GFP level is proportional to TCR signal strength, we observed that OX40 and GITR expression by Tregs positively correlates with Nur77-GFP expression; this suggests that those thymocytes perceiving the strongest TCR signals during development are engendered with the highest level of expression of these TNFRSF members. Importantly, the ligands for these receptors are expressed on APCs in the thymus. To identify the functional role these TNFRSF members play in thymic Treg development, we made mixed bone marrow chimeras with WT and Gitr-/- bone marrow. Gitr-/- donor cells gave rise to normal numbers of CD4+CD25+FOXP3- Treg progenitors but exhibited an ~30% decrease in FOXP3+ mature thymic Tregs relative to WT donor cells. Furthermore, in vitro stimulation of Treg progenitors with GITRL or OX40L leads to a marked enhancement of Treg differentiation. We are presently investigating whether GITR, OX40 and TNFR2 play partially redundant roles in driving thymic Treg development by generating Ox40-/- x Gitr-/- mice in conjunction with neutralizing antibodies to TNFR2.
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