Dominant role of the α-chain in rejection of tumor cells bearing a specific alloantigen in TCRα transgenic mice and in in vitro experiments.

Maria Zamkova,Alexey Deikin,Ludmila Khromykh,Dmitry Kazansky,Alexandra Bruter,Yuliya Silaeva,Nadezhda Persiyantseva,Anastasiya Kalinina

doi:10.18632/oncotarget.27093

Abstract

Both TCRα and TCRβ types of T-cell receptors contribute to antigen recognition. However, some TCRs have chain centricity, which means that either the α-chain or the β-chain dictates the peptide–MHC complex specificity. Most earlier reports investigated the role of well-studied β-chains in antigen recognition by TCRαβ. In a previous study, we identified TCRs specific to the H-2Kb molecule. In the present work, we generated transgenic mice carrying the α-chain of this TCR. We found that these transgenic mice rejected EL-4 tumor cells bearing alloantigen H-2Kb more effectively than wild-type mice and similarly to mice with established specific memory T cells. Moreover, we found that T cells transduced with this TCRα can inhibit EL-4 cell growth in vitro and in vivo. We also found that transgenic mice recruit fewer CD8 T cells into the peritoneal cavity at the peak of the immune response and had a significantly higher number of central memory CD8 T cells in the spleen of intact transgenic mice compared to intact wild-type control. These results indicate the ability of a single transgenic α-chain of the H-2Kb-specific TCR to determine specific recognition of the H-2Kb molecule by a repertoire of T lymphocytes and to rapidly reject H-2Kb-bearing lymphoma cells.

Highlights

Each T cell has one or less often two types of T-cell receptors (TCRs) on its surface
It was shown that CDR1 and CDR2 interact with a Major histocompatibility complex (MHC) molecule, and the highly variable CDR3 contacts with the unique peptide component of a peptide–MHC complex (pMHC) [2]
As green fluorescent protein (GFP) transcript length is similar to the length of α-chain and it was cloned into the same vector, we assumed that the efficiency of GFP transduction is the same as the efficiency of α-chain transduction

Summary

Introduction

Each T cell has one or less often two types of T-cell receptors (TCRs) on its surface. The TCR is composed of α- and β-chains. As allelic exclusion of the β-chain occurs, only one β-chain can be rearranged in a single T cell. Due to the lack of α-chain allelic exclusion, some mature T cells can express two different TCR α-chains [1]. Both TCRα and TCRβ contain constant (Cα and Cβ, respectively), variable (Vα and Vβ, respectively), joining (Jα and Jβ, respectively) and, in the case of TCRβ, diversity (D) regions. Three extremely variable regions called complementarity-determining regions (CDRs), which are present in both α- and β-chains, are responsible for the TCR specificity. We should mention that studies describing TCR chain recombination were done using murine models. The structure of TCR loci is similar in mice and humans; a number of studies describe the level of sequence similarity of TCR repertoires between mouse and human [3, 4]

Methods

Results

Conclusion