Role of interleukin 2 in the development of MHC class II -restricted thymocytes

Abstract

While TCR:MHC interactions play an essential role in determining the fate of developing thymocytes during selection, the types of APC, costimulatory inputs, and soluble factors encountered by these thymocytes may also modulate the final outcome. Although IL2 had been proposed as a growth factor for developing thymocytes due to its proliferative effect on peripheral T cells, recent evidence implicates IL2 in limiting peripheral T cell responses via AIM Indeed, the T cell-mediated autoimmune disorders that spontaneously develop in IL2−/− and IL2Rα−/− mice may be consequences of an inability of peripheral CD4 T cells to undergo AICD. Whether IL2 plays a similar limiting role in the thymus is unknown. We examined the consequences of IL2-deficiency on thymic architecture and thymocyte development, and investigated the developmental potential of IL2−/− thymocytes within a normal thymic microenvironment. In considering the consequences of the loss of IL2 on thymocyte negative selection, we find that TCR engagement results in the induction of thymocyte apoptosis concomitant with in situ IL2 production, expression of high affinity IL2Rs, and internalization of IL2 protein. These findings demonstrate that the inefficient anti-CD3 mediated thymocyte apoptosis observed in IL2 −/− mice is consistent with a role for IL2/IL2R interactions in the negative selection of thymocytes. Moreover, the restoration of cortical thymocyte apoptosis upon administration of exogenous IL2 and the inhibition of Ag-mediated thymocyte apoptosis in TCR-transgenic mice following administration of IL2R-blocking antibodies strongly corroborates this hypothesis. Our results also suggest that the maximal production of IL2 involves a complex interaction between thymic APC, immature, and mature thymocytes—an interaction which underscores the importance of intact thymic microarchitecture in ensuring efficient thymocyte negative selection. When combined with the finding that IL2 is required for the maintenance of some thymic APC populations, our results help explain the loss of immature thymocytes observed in older IL2 −/− mice. We conclude by presenting a model to explain the multiple roles of IL2 in thymocyte development, the consequences of its loss on central and peripheral tolerance, and the candidate cellular elements and environmental niches necessary for the efficient removal of autoreactive thymocytes