IL-2 dependent genes of T regulatory and T effector cells

Interleukin-2 receptor (IL-2R) signaling is essential for T regulatory (Treg) cell development and homeostasis. Here we show that expression of IL-2Rbeta chains that lack tyrosine residues important for the association of the adaptor Shc and the transcription factor STAT5 in IL-2Rbeta-deficient mice resulted in production of a normal proportion of natural Treg cells that suppressed severe autoimmunity related with deficiency in IL-2 or IL-2R. These mutant IL-2Rbeta chains supported suboptimal and transient STAT5 activation that upregulate the transcription factor Foxp3 to normal amounts in natural, but not induced, Treg cells. Using cells T cell obtained from normal C57BL/6 mice and mice harboring Treg cells with impaired IL-2R signaling, gene expression profiling revealed many targets in peripheral natural Treg cells that were IL-2-dependent and a substantial overlap between the Treg cell IL-2-dependent gene program and the Treg cell transcriptional signature. Collectively, these findings demonstrate that a critical, and perhaps minor, subset of IL-2-dependent targets in Treg cells is indexed to a low IL-2R signaling threshold and that a substantial proportion of the Treg cell gene program is regulated by IL-2. CD4 T effector cells also showed many IL-2R-dependent gene and these also overlapped in a distintive manner with the IL-2-dependent genes of Treg cells and the Treg gene signature. For each strain, we analyzed two cell populations, freshly isolated Treg cells and T effector cells. These latter cells were obtained after spleen cells activated with anti-CD3 for 48 hr and then isolating the CD4+ CD25+ activated effector T cells. The IL-2R defective T cells were obtained from C57BL/6-2Rbeta-WT/thymus transgenic mice after breeding to IL-2Rbeta-deficient mice. Each sample consisted of 3 distinct biological replicates. After GC-RMA normalization, intensity values were average for the replicates within the groups. We compared the differentially expressed genes within each group and these differential expressed genes were then compared between each other and Treg gene signature.