ABSTRACT
Expression and signalling through the pre-TCR and the TCRalphabeta resemble two critical checkpoints during T cell development. We investigated to which extent a pre-TCR can functionally replace mature TCRalpha chains during T cell development. For this purpose, transgenic mice were generated expressing the pre-TCRalpha (pTalpha) under the transcriptional control of TCRbeta regulatory elements. We report here on the interesting finding that constitutive pTalpha expression allows complete T cell maturation. The pre-TCR complex permits a subset of beta-selected thymocytes to mature in the absence of TCRalpha into peripheral T cells (betaT cells) comprising up to 10% of all lymphocytes. Lymphopenia-driven proliferation of these betaT cells is similar to that of conventional alphabetaT cells. Furthermore, betaT cells proliferated and acquired effector function upon stimulation with allogeneic MHC.
Subject(s)
Cell Differentiation/immunology , Gene Expression Regulation/immunology , Genes, T-Cell Receptor alpha/immunology , Genes, T-Cell Receptor beta/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , T-Lymphocytes/immunology , Animals , Cell Differentiation/genetics , Cell Proliferation , Gene Expression Regulation/genetics , Genes, T-Cell Receptor alpha/genetics , Genes, T-Cell Receptor beta/genetics , Lymphopenia/genetics , Lymphopenia/immunology , Major Histocompatibility Complex/genetics , Major Histocompatibility Complex/immunology , Mice , Mice, Knockout , Receptors, Antigen, T-Cell, alpha-beta/genetics , Response Elements/genetics , Response Elements/immunology , Signal Transduction/genetics , Signal Transduction/immunologyABSTRACT
Gimap4, a member of the newly identified GTPase of the immunity-associated protein family (Gimap), is strongly induced by the pre-T-cell receptor in precursor T lymphocytes, transiently shut off in double-positive thymocytes, and reappears after TCR-mediated positive selection. Here, we show that Gimap4 remains expressed constitutively in the cytosol of mature T cells. A C-terminal IQ domain binds calmodulin in the absence of calcium, and conserved PKC phosphorylation motifs are targets of concanavalin A (ConA)- or PMA/ionomycin-induced PKC activation. To address the role of Gimap4 in T-cell physiology, we completed the genomic organization of the gimap4 locus and generated a Gimap4-null mutant mouse. Studies in these mice revealed no critical role of Gimap4 in T-cell development but in the regulation of apoptosis. We have found that Gimap4 accelerates the execution of programmed cell death induced by intrinsic stimuli downstream of caspase-3 activation and phosphatidylserine exposure. Apoptosis directly correlates with the phosphorylation status of Gimap4.
