The molecular events of T cell positive selection in the thymus

Development of thymocytes within the thymic microenvironment allows immature T cells to receive many differentiation signals, thus ensuring that functionally mature CD4 and CD8 T cells can respond appropriately to antigen stimulation upon emigration to the periphery. CD4+CD8+ thymocytes receive signals through their T cell receptors (TCR) following self-antigen/major histocompatibility complex (MHC) engagement on thymic stromal cells in combination with additional signals received from stromal cells. These signals result in the activation of a diverse transcriptional program regulating thymocyte survival, TCR gene recombination, MHC allelic exclusion, migration from the cortical to medullary thymic microenvironment, tuning of TCR responsiveness to antigen stimulation, and commitment to and differentiation into the helper or killer T cell lineage. We performed differential gene microarray analysis on thymocytes that have or have not received a TCR signal in order to determine potential regulators of the processes initiated following positive selection. We found many novel gene changes are initiated following positive selection of CD4+CD8+ thymocytes and discuss some of these gene changes with respect to the major processes of positive selection. A number of molecules involved in Transforming Growth Factor beta (TGF-beta) signaling were found to be upregulated during positive selection. To further address the roles of these molecules during thymocyte development, we characterized their expression in T lineage cells. We present evidence that downstream signaling may be modified through the expression of an alternate TGF-beta receptor complex on developing T cells. We propose that this may have profound effects on the transcriptional regulation of target genes among T lineage cells during the development of T cells in the thymus as well as during adaptive immune responses in the periphery.