The role of the T cell antigen receptor complex (TCR) in alphabeta/gammadelta lineage commitment remains controversial, in particular whether different TCR isoforms intrinsically favor adoption of a certain lineage. Here, we demonstrate that impairing the signaling capacity of a gammadeltaTCR complex enables it to efficiently direct thymocytes to the alphabeta lineage. In the presence of a ligand, a transgenic gammadeltaTCR mediates almost exclusive adoption of the gammadelta lineage, while in the absence of ligand, the same gammadeltaTCR promotes alphabeta lineage development with efficiency comparable to the pre-TCR. Importantly, attenuating gammadeltaTCR signaling through Lck deficiency causes reduced ERK1/2 activation and Egr expression and diverts thymocytes to the alphabeta lineage even in the presence of ligand. Conversely, ectopic Egr overexpression favors gammadelta T cell development. Our data support a model whereby gammadelta versus alphabeta lineage commitment is controlled by TCR signal strength, which depends critically on the ERK MAPK-Egr pathway.

SUMMARY αβ and γδ T-cells arise from a common thymocyte progenitor during development in the thymus. Emerging evidence suggests that the pre-T cell receptor (pre-TCR) and γδ T-cell receptor (γδTCR) play instructional roles in specifying the αβ and γδ T-lineage fates, respectively. Nevertheless, the signaling pathways differentially engaged to specify the fate and promote the development of these lineages remain poorly understood. Here we show that differential activation of the ERK - early growth response gene (Egr) - inhibitor of DNA binding 3 (Id3) pathway plays a defining role in this process. In particular, Id3 expression serves to regulate adoption of the γδ fate. Moreover, Id3 is both necessary and sufficient to enable γδ-lineage cells to differentiate independently of Notch signaling and become competent IFNγ-producing effectors. Taken together, these findings identify Id3 as a central player that controls both adoption of the γδ fate and their maturation in the thymus.

The alphabeta and gammadelta T lineages are thought to arise from a common precursor; however, the regulation of separation and development of these lineages is not fully understood. We report here that development of alphabeta and gammadelta precursors was differentially affected by elimination of ribosomal protein L22 (Rpl22), which is ubiquitously expressed but not essential for translation. Rpl22 deficiency selectively arrested development of alphabeta-lineage T cells at the beta-selection checkpoint by inducing their death. The death was caused by induction of p53 expression, because p53 deficiency blocked death and restored development of Rpl22-deficient thymocytes. Importantly, Rpl22 deficiency led to selective upregulation of p53 in alphabeta-lineage thymocytes, at least in part by increasing p53 synthesis. Taken together, these data indicate that Rpl22 deficiency activated a p53-dependent checkpoint that produced a remarkably selective block in alphabeta T cell development but spared gammadelta-lineage cells, suggesting that some ribosomal proteins may perform cell-type-specific or stage-specific functions.

These results show that ILCs are present in human skin and indicate that RORγt(+) CD56(+) ILC3 may be involved in the pathogenesis of psoriasis.

The active form of vitamin D3, 1,25(OH)2D3, has significant immunomodulatory properties and is an important determinant in the differentiation of CD4+ effector T cells. The biological actions of 1,25(OH)2D3 are mediated by the vitamin D receptor (VDR) and are believed to correlate with the VDR protein expression level in a given cell. The aim of this study was to determine if and how 1,25(OH)2D3 by itself regulates VDR expression in human CD4+ T cells. We found that activated CD4+ T cells have the capacity to convert the inactive 25(OH)D3 to the active 1,25(OH)2D3 that subsequently up-regulates VDR protein expression approximately 2-fold. 1,25(OH)2D3 does not increase VDR mRNA expression but increases the half-life of the VDR protein in activated CD4+ T cells. Furthermore, 1,25(OH)2D3 induces a significant intracellular redistribution of the VDR. We show that 1,25(OH)2D3 stabilizes the VDR by protecting it from proteasomal degradation. Finally, we demonstrate that proteasome inhibition leads to up-regulation of VDR protein expression and increases 1,25(OH)2D3-induced gene activation. In conclusion, our study shows that activated CD4+ T cells can produce 1,25(OH)2D3, and that 1,25(OH)2D3 induces a 2-fold up-regulation of the VDR protein expression in activated CD4+ T cells by protecting the VDR against proteasomal degradation.