of April 18 , 2017 . This information is current as T Cells + Mature CD 8 Positive Selection by the Pre - TCR Yields

It has been of much interest whether there is functional redundancy between the constitutively signaling pre-T␣/TCR␤ (pre-TCR) and ligated TCR␣␤ complexes, which independently operate the two distinct checkpoints during thymocyte development, i.e., the pre-TCR involved in ␤-selection at the CD4 ؊ CD8 ؊ double-negative stage and the TCR␣␤ being crucial for positive/negative selection at the CD4 ؉ CD8 ؉ double-positive stage. We found that the pre-TCR expressed on double-positive cells in TCR␣-deficient (TCR␣ ؊/؊) mice produced a small number of mature CD8 ؉ T cells. Surprisingly, when pre-T␣ was overexpressed, resulting in augmentation of pre-TCR expression, there was a striking increase of the CD8 ؉ T cells. In addition, even in the absence of up-regulation of pre-TCR expression, a similar increase of CD8 ؉ T cells was also observed in TCR␣ ؊/؊ mice over-expressing Egr-1, which lowers the threshold of signal strength required for positive selection. In sharp contrast, the CD8 ؉ T cells drastically decreased in the absence of pre-T␣ on a TCR␣ ؊/؊ background. Thus, the pre-TCR appears to functionally promote positive selection of CD8 ؉ T cells. The biased production of CD8 ؉ T cells via the pre-TCR might also support the potential involvement of signal strength in CD4/CD8 lineage commitment. T he development of T cells in the thymus is controlled at two consecutive checkpoints (1, 2). At the first checkpoint , termed ␤-selection, CD4 Ϫ CD8 Ϫ double-negative thymocytes with a productive TCR␤ rearrangement are rescued from programmed cell death by the pre-TCR consisting of the varied TCR␤ and the invariant pre-TCR␣ (pT␣) 4 chain. As a result , the cells proliferate, and begin to coexpress CD4 and CD8 and to rearrange the TCR␣ locus. Some evidence suggests that the pre-TCR is also involved in channeling cells into the ␣␤-lineage because it reduces the number of ␥␦ T cells with productive TCR␤ rearrangements (3, 4). At the second checkpoint, the engagement of the TCR␣␤ by appropriate MHC ligands rescues CD4 ϩ CD8 ϩ double-positive (DP) thymocytes from apoptotic death, resulting in the generation of mature CD4 ϩ CD8 Ϫ or CD4 Ϫ CD8 ϩ single-positive (SP) thymocytes. Very interestingly, there exists an obvious similarity of proximal signaling events between the constitutively signaling pre-TCR and the ligated TCR␣␤, resulting in tyrosine phosphorylation of CD3␨ and CD3⑀ subunits, recruitment and phosphorylation of ZAP-70 and syk protein kinases, activation of the ras/mitogen-activated protein kinase pathway, and rapid increase …