Toward a Molecular Understanding of Adaptive Immunity: A Chronology, Part III.

Kendall A Smith

doi:10.3389/fimmu.2014.00029

Abstract

Early reports on T cell antigen receptor (TCR) signaling uncovered a rapid increase in intracellular calcium concentration and the activation of calcium-dependent protein kinase as necessary for T cell activation. Cytolytic T cell clones were instrumental in the discovery of intracellular cytolytic granules, and the isolation of the perforin and granzyme molecules as the molecular effectors of cell-mediated lysis of target cells via apoptosis. Cytolytic T cell clones and TCR cDNA clones were also instrumental for the generation of TCR transgenic animals, which provided definitive evidence for negative selection of self-reactive immature thymocytes. In addition, studies of TCR complex signaling of immature thymocytes compared with mature T cells were consistent with the interpretation that negative selection occurs as a consequence of the incapacity of immature cells to produce IL-2, resulting in cytokine deprivation apoptosis. By comparison, taking advantage of cloned TCRs derived from T cell clones reactive with male-specific molecules, using TCR transgenic mice it was possible to document positive selection of female thymocytes when the male-specific molecules were absent. Focusing on the molecular mechanisms of T cell “help” for the generation of antibody-forming cells following the path opened by the elucidation of the IL-2 molecule, several groups were successful in the identification, isolation, and characterization of three new interleukin molecules (IL-4, IL-5, and IL-6) that promote the proliferation and differentiation of B cells. In addition, the identification of a B cell surface molecule (CD40) that augmented B cell antigen receptor-stimulated proliferation and differentiation led to the discovery of a T cell activation surface molecule that proved to be the CD40-ligand, thus finally providing a molecular explanation for “linked or cognate” recognition when T cells and B cells interact physically. Accordingly, the decade after the generation of the first T cell clones saw the elucidation of the molecular mechanisms of T cell cytotoxicity and T cell help, thereby expanding the number of molecules responsible for adaptive T cell immunity.

Highlights

Reports on T cell antigen receptor (TCR) signaling uncovered a rapid increase in intracellular calcium concentration and the activation of calcium-dependent protein kinase as necessary for T cell activation
The CD4CD8 double-positive thymocytes undergo negative selection when triggered via their TCR/CD3 complex by self-peptide/major histocompatibility complex (MHC) complexes in vivo, but the TCR/CD3 complex expressed by these cells appears immature, incapable of promoting transcription and translation of genes such as IL-2 and the IL-2Rα-chain, which are required for a proliferative response by mature peripheral single-positive www.frontiersin.org
The biochemical analysis of antigen-specific TCR signaling revealed that lymphocytes are excitable cells, not too different from neuromuscular cells that react to their molecular environment by signaling through their lipid membranes, leading to ion fluxes and activation of phosphorylating enzyme cascades that regulate the genetic expression of the cells

Summary

Introduction

Reports on T cell antigen receptor (TCR) signaling uncovered a rapid increase in intracellular calcium concentration and the activation of calcium-dependent protein kinase as necessary for T cell activation. These findings were interpreted as providing “unequivocal evidence that expression of a particular V β segment confers preferential T cell reactivity in vitro to Mls-encoded determinants and that TCRs using V β6 are selected against in the thymus of mice that express Mls-encoded gene products.” they felt that, consistent with Burnet’s proposal, tolerance is mediated by the deletion of self-reactive clones rather than by alternative mechanisms such as anergy or peripheral suppression.

Results

Conclusion