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LAT signalling pathology: a T-cell dependent, B cell autoimmune condition without T cell self-reactivity
If you have a question about this talk, please contact Sue Griffin.
Host: Chris Rudd (email@example.com)
When the T-cell receptor (TCR) recognizes antigens, the CD3 chains of the TCR complex are phosphorylated by the Src family kinase Lck. This allows the recruitment of the protein tyrosine kinase ZAP -70 that in turn phosphorylates several intracellular substrates, including the LAT adaptor. Upon tyrosine phosphorylation, LAT nucleates the assembly of a multiprotein complex – the LAT signalosome – that bridges the T cell-specific and the ubiquitous components of the signaling pathways that control many aspects of T cell development and function. Partial loss-of-function mutations in several molecules involved in TCR signaling (ZAP-70, LAT ) result in inflammation and autoimmunity.
How can mutations that reduce TCR signaling output paradoxically lead to immune pathologies? We will summarize recent data demonstrating that mutations in LAT predispose toward aberrant T cell responses to antigen in the presence of normal thymic selection. In the absence of LAT , the activity of the Lck kinase appears sustained without the need for TCR engagement.
As a consequence, in the absence of LAT , antigen-specific T cell responses evolve into pro-inflammatory responses that unfold in a TCR -independent manner and induce the production of autoantibodies in a “quasi-mitogenic” mode. Therefore, some pathological conditions called “autoimmune” might not result from the presence of self-reactive T cells but from defect in mechanisms that normally keep protein tyrosine kinase activity in check.
This talk is part of the Immunology in Pathology series.
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