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TCR Transmembrane Tyrosines Are Required for Pre-TCR Function¹

Jerome H. Holland Laboratory for Biomedical Research, American Red Cross, Rockville, MD 20855

The pre-TCR promotes thymocyte development in the lineage. Productive rearrangement of the TCR locus triggers the assembly of the pre-TCR, which includes the pT chain and CD3 subunits. This complex receptor signals the up-regulation of CD4 and CD8 expression, thymocyte proliferation/survival, and the cessation of TCR rearrangements (allelic exclusion). In this study, we investigate the function of two conserved tyrosine residues located in the TCR chain transmembrane region of the pre-TCR. We show that replacement of both tyrosines with alanine and expression of the mutant receptor in RAG-1^null thymocytes prevents surface expression and abolishes pre-TCR function relative to wild-type receptor. Replacement of both tyrosines with phenylalanines (YF double mutant) generates a complex phenotype in which thymocyte survival and proliferation are severely disrupted, differentiation is moderately disrupted, and allelic exclusion is unaffected. We further show that the YF double mutant receptor is expressed on the cell surface and associates with pT and CD3 at the same level as does wild-type TCR, while association of the YF double mutant with CD3 is slightly reduced relative to wild type. These data demonstrate that pre-TCR signaling pathways leading to proliferation and survival, differentiation, and allelic exclusion are differently sensitive to subtle mutation-induced alterations in pre-TCR structure.

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