How the Discovery of the CD4/CD8-p56lck Complexes Changed Immunology and Immunotherapy.

Christopher E Rudd

doi:10.3389/fcell.2021.626095

Abstract

The past 25 years have seen enormous progress in uncovering the receptors and signaling mechanisms on T-cells that activate their various effecter functions. Until the late 1980s, most studies on T-cells had focused on the influx of calcium and the levels of cAMP/GMP in T-cells. My laboratory then uncovered the interaction of CD4 and CD8 co-receptors with the protein-tyrosine kinase p56lck which are now widely accepted as the initiators of the tyrosine phosphorylation cascade leading to T-cell activation. The finding explained how immune recognition receptors expressed by many immune cells, which lack intrinsic catalytic activity, can transduce activation signals via non-covalent association with non-receptor tyrosine kinases. The discovery also established the concept that a protein tyrosine phosphorylation cascade operated in T-cells. In this vein, we and others then showed that the CD4- and CD8-p56lck complexes phosphorylate the TCR complexes which led to the identification of other protein-tyrosine kinases such as ZAP-70 and an array of substrates that are now central to studies in T-cell immunity. Other receptors such as B-cell receptor, Fc receptors and others were also subsequently found to use src kinases to control cell growth. In T-cells, p56lck driven phosphorylation targets include co-receptors such as CD28 and CTLA-4 and immune cell-specific adaptor proteins such as LAT and SLP-76 which act to integrate signals proximal to surface receptors. CD4/CD8-p56lck regulated events in T-cells include intracellular calcium mobilization, integrin activation and the induction of transcription factors for gene expression. Lastly, the identification of the targets of p56lck in the TCR and CD28 provided the framework for the development of chimeric antigen receptor (CAR) therapy in the treatment of cancer. In this review, I outline a history of the development of events that led to the development of the “TCR signaling paradigm” and its implications to immunology and immunotherapy.

Highlights

The last decades have witnessed major advances in the identification of the receptors and signaling pathways that control the activation and differentiation of T-cells
From the outset of our work in 1986, we found that immune precipitates of CD4 and CD8 possessed an unusually high level of endogenous tyrosine kinase activity that was not observed in the precipitates of other receptors
Called “T bodies,” almost 30 years ago, by Gross et al (1989), chimeric antigen receptor (CAR) use antigen-recognition domains derived from an antibody or other proteins that are linked to a transmembrane domain and a intracellular cytoplasmic tail that contains the immuno-receptor tyrosine-based activation motifs (ITAMs) from CD3 or TCR-zeta cytoplasmic tails (Figure 5)

Summary

INTRODUCTION

The last decades have witnessed major advances in the identification of the receptors and signaling pathways that control the activation and differentiation of T-cells. There were no known surface receptors with endogenous protein-kinase domains connected to the antigen-receptor (TCR/CD3 complex) and little evidence of tyrosine phosphorylation in immune cells. Cells) and SLP-76 (SH2-domain-containing leukocyte protein of 76 kD) This fits with the notion that the p56lck is responsible for the main wave of tyrosine phosphorylation cascade of numerous substrates that includes ZAP-70 with a more specialized function in phosphorylating a limited additional number of key substrates needed for specific functions such as calcium mobilization. Part of the overall cascade includes immune cell-specific adaptors, proteins that lack enzymatic activities, and instead are made up of domains or sites that mediate complex formation (Rudd, 1999) They are considered types of molecular switches which integrate proximal signaling with downstream events. PI 3K, in turn, catalyzes the production of PI-3P from PI and PI 3,4-P2 from PI 4P,

Cellular functions

OTHER PROTEIN TYROSINE KINASES

Findings

SUMMARY