Department of Chemistry
Host: Ann McDermott
Title: The Critical Role of Tyrosine Kinase Sequence Specificity in T Cell Activation
Abstract: T cells respond to foreign antigens with remarkable selectivity. The fidelity of T cells cannot be fully explained by differences in the affinities of cognate and non-cognate antigens for the T cell antigen receptor (TCR). Thus, this fidelity must be encoded in downstream signaling steps, many of which are driven by cytoplasmic tyrosine kinases. I will discuss our research examining the role of tyrosine kinase sequence specificity in controlling the architecture of the primary signaling pathway downstream of the T cell receptor. This work was enabled by the development of high-throughput platform to profile tyrosine kinase specificity that combines bacterial surface-display of peptide libraries with cell sorting and deep sequencing. Specificity screens using this platform revealed a unique substrate selection mechanism that enforces tight control in the initiating steps of TCR signaling. They also led to the identification of an unexpected kinetic bottleneck in the TCR pathway that controls T cell sensitivity toward weak agonists and self-antigens. The presence of this slow signaling step, which is governed by kinase sequence specificity, strongly supports a kinetic proofreading model to explain T cell antigen selectivity.