Constitutive expression of the pre-TCR enables development of mature T cells

Expression and signalling through the pre-TCR and the TCRαβ resemble two critical checkpoints during T cell development. We investigated to which extent a pre-TCR can functionally replace mature TCRα chains during T cell development. For this purpose, transgenic mice were generated expressing the pre-TCRα (pTα) under the transcriptional control of TCRβ regulatory elements. We report here on the interesting finding that constitutive pTα expression allows complete T cell maturation. The pre-TCR complex permits a subset of β-selected thymocytes to mature in the absence of TCRα into peripheral T cells (βT cells) comprising up to 10% of all lymphocytes. Lymphopenia-driven proliferation of these βT cells is similar to that of conventional αβT cells. Furthermore, βT cells proliferated and acquired effector function upon stimulation with allogeneic MH

PIM1 reconstitutes thymus cellularity in interleukin 7- and common gamma chainmutant mice and permits thymocyte maturation in Rag- but not CD3gammadeficient mice

The majority of lymphomas induced in Rag-deficient mice by Moloney murine leukemia virus (MoMuLV) infection express the CD4 and/or CD8 markers, indicating that proviral insertions cause activation of genes affecting the development from CD4�8 � pro-T cells into CD4�8 � pre-T cells. Similar to MoMuLV wild-type tumors, 50 % of CD4�8 � Rag-deficient tumors carry a provirus near the Pim1 protooncogene. To study the function of PIM proteins in T cell development in a more controlled setting, a Pim1 transgene was crossed into mice deficient in either cytokine or T cell receptor (TCR) signal transduction pathways. Pim1 reconstitutes thymic cellularity in interleukin (IL)-7 – and common � chain–deficient mice. In Pim1-transgenic Rag-deficient mice but notably not in CD3�-deficient mice, we observed slow expansion of the CD4�8 � thymic compartment to almost normal size. Based on these results, we propose that PIM1 functions as an efficient effector of the IL-7 pathway, thereby enabling Rag-deficient pro-T cells to bypass the pre-TCR–controlled checkpoint in T cell development. Key words: common � chain • IL-7 • Rag • proviral tagging • lymphomagenesis • pre-T cell development Intrathymic development of lymphoid precursors into mature �/ � T cells takes place in a series of distinct maturation steps that depend on the signaling pathways of antigen and cytokine receptors (for review see references 1 and 2). Each stage is defined by a unique pattern of gene expression and specific surface markers. For the differentiation and expansion of CD4�8 � (double negative [DN]) 1 pro-T cells that have their TCR genes in germline configuration, the IL-7R appears to be most critical. The IL-7R comprises the IL-7R � chain (CD127) and the common cytokine receptor � chain (�c, CD132). The latter is also a constituent of th