SIT and TRIM two redundant adaptor molecules in T cell development: analysis of the biological relevance of the TBSMs. DFG -GRK 1167
SIT (SHP-2-Interacting Transmembrane adaptor protein) and TRIM (T-cell Receptor Interacting Molecule) are non-raft associated homodimeric transmembrane adapter proteins strongly expressed in T lymphocytes. Both molecules carry several tyrosine-based signalling motifs (TBSMs) within their cytoplasmic domains two of which are highly conserved between the two molecules (YGNL and YASV in SIT, and YGNL and YASL in TRIM). SIT acts as a negative regulator of TCR-mediated signalling. Indeed, SIT-deficient mice display (i) enhanced positive selection and a shift from positive toward negative selection, (ii) hyperresponsiveness to anti-CD3 stimulation, and (iii) a more pronounced incidence and severity of Experimental Autoimmune Encephalomyelitis (EAE). Conversely to SIT, TRIM seems to be dispensable in lymphocyte development. To further assess the role of SIT and TRIM in T-cell, we established SIT-TRIM double knock-out (dKO) mice. Thymus development is markedly altered in the absence of SIT and TRIM and represents in part a magnification of the defects observed in SIT-/- mice. When crossed into the H-Y TCR transgenic mice, most of positive selection is diverted to negative selection. Thus, it appears that SIT and TRIM together negatively regulate the TCR-mediated signalling threshold required for positive selection. The aim of this project is to study the molecular mechanisms of SIT and TRIM redundancy in fine tuning signals emanating from the TCR
SIT, TCR transgenic mice, TRIM, Thymic development, knockout mice, negative selection, positive selection, transmembrane adaptor
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