Aberrant TCR-mediated signaling in CD45-null thymocytes involves dysfunctional regulation of Lck, Fyn, TCR-zeta, and ZAP-70.
CD45 is a transmembrane phosphotyrosine phosphatase expressed on all nucleated hemopoietic cells. Targeting of CD45 exon 9 has generated a mouse line completely lacking CD45 expression (CD45-null) in which there are severe abnormalities in T cell development. Defects in TCR-mediated signals underlying these abnormalities have now been investigated using CD45-null T cells. No T cell proliferation was detected in response to a CD3 mAb. In thymocytes the p56(lck) and p59(fyn) tyrosine kinases were hyperphosphorylated, and p56(lck) was in its inactive conformation. Both basal and TCR-stimulated tyrosine phosphorylation of TCR-zeta and CD3-epsilon were much reduced, and TCR stimulation induced an abnormal p18 phosphoisomer of TCR-zeta previously noted in T cells stimulated by altered peptide ligands. These defects were associated with the failure of ZAP-70 kinase recruitment to the TCR-zeta chain. TCR coupling to the tyrosine phosphorylation of several proteins, including HS1 and p120(cbl), was also much reduced. However, TCR-induced signaling was not ablated, and significant inositol phosphate and calcium signals were observed in CD45-null thymocytes. Our molecular analysis suggests that the threshold for TCR signal transduction is greatly increased in CD45-null T cells, thus explaining the profound defects in thymic development.[1]References
- Aberrant TCR-mediated signaling in CD45-null thymocytes involves dysfunctional regulation of Lck, Fyn, TCR-zeta, and ZAP-70. Stone, J.D., Conroy, L.A., Byth, K.F., Hederer, R.A., Howlett, S., Takemoto, Y., Holmes, N., Alexander, D.R. J. Immunol. (1997) [Pubmed]
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