Adapting T Cell Receptor Ligand Discrimination Capability via LAT.

Arthur Weiss,Wan-Lin Lo

doi:10.3389/fimmu.2021.673196

Abstract

Self- and non-self ligand discrimination is a core principle underlying T cell-mediated immunity. Mature αβ T cells can respond to a foreign peptide ligand presented by major histocompatibility complex molecules (pMHCs) on antigen presenting cells, on a background of continuously sensed self–pMHCs. How αβ T cells can properly balance high sensitivity and high specificity to foreign pMHCs, while surrounded by a sea of self-peptide ligands is not well understood. Such discrimination cannot be explained solely by the affinity parameters of T cell antigen receptor (TCR) and pMHC interaction. In this review, we will discuss how T cell ligand discrimination may be molecularly defined by events downstream of the TCR–pMHC interaction. We will discuss new evidence in support of the kinetic proofreading model of TCR ligand discrimination, and in particular how the kinetics of specific phosphorylation sites within the adaptor protein linker for activation of T cells (LAT) determine the outcome of TCR signaling. In addition, we will discuss emerging data regarding how some kinases, including ZAP-70 and LCK, may possess scaffolding functions to more efficiently direct their kinase activities.

Highlights

The immune system maintains a homeostatic state within an organism while remaining poised to vigorously respond to life-threatening challenges
The T cell antigen receptor (TCR) is the major surface receptor used by every T cell to survey host cells expressing short self-peptides derived from host self-proteins bound to self-MHC molecules
The finding that most tetrapods have a comparable glycine at the homologous position in linker for activation of T cells (LAT) which is likely to lead to slow activation of phospholipase Cg1 (PLCg1) [50], but that other phosphorylation sites in LAT and even within SLP76 are better substrates for z chain-associated protein kinase 70 (ZAP-70) [74], emphasizes the critical importance of Y132 as a critical timer to assess whether T cells should be fully activated to respond to potential threats in most warm-blooded organisms

Summary

Introduction

The immune system maintains a homeostatic state within an organism while remaining poised to vigorously respond to life-threatening challenges. The Src family kinase (SFK) LCK and z chain-associated protein kinase 70 (ZAP-70), as two proximal and essential T cell specific kinases in TCR signal initiation, have attracted great interest regarding their supportive roles in kinetic proofreading.

Results

Conclusion