Preferential HLA-B27 Allorecognition Displayed by Multiple Cross-Reactive Antiviral CD8+ T Cell Receptors.

Louise C Rowntree,Lloyd J D'Orsogna,Jamie Rossjohn,Tom C Kotsimbos,Jessica Sun,Thi H O Nguyen,Frans H J Claas,Nicole A Mifsud,Anthony W Purcell,Heleen Van Den Heuvel

doi:10.3389/fimmu.2020.00248

Abstract

T cells provide essential immunosurveillance to combat and eliminate infection from pathogens, yet these cells can also induce unwanted immune responses via T cell receptor (TCR) cross-reactivity, also known as heterologous immunity. Indeed, pathogen-induced TCR cross-reactivity has shown to be a common, robust, and functionally potent mechanism that can trigger a spectrum of human immunopathologies associated with either transplant rejection, drug allergy, and autoimmunity. Here, we report that several virus-specific CD8+ T cells directed against peptides derived from chronic viruses (EBV, CMV, and HIV-1) presented by high frequency HLA-A and -B allomorphs differentially cross-react toward HLA-B27 allotypes in a highly focused and hierarchical manner. Given the commonality of cross-reactive T cells and their potential contribution to adverse outcomes in allogeneic transplants, our study demonstrates that multiple antiviral T cells recognizing the same HLA allomorph could pose an extra layer of complexity for organ matching.

Highlights

A hallmark of human antiviral T cells is their ability to recognize viral peptide antigen bound to a self-human leukocyte antigen (HLA) on the surface of infected cells
CD8+ T cell clones raised against the HIV-1 B57TW10 epitope in patients A16 and 457 showed very high frequencies following tetramer-specific Peripheral blood mononuclear cells (PBMC) bulk sorting (Figure 1C, middle panels), which were similar to the high frequencies observed against the EBV-B∗07:02-restricted EBNA-3A-derived RPPIFIRRL (B7RPP) epitope (i.e., HD9G6)
We examined the cross-reactive potential of CD8+ T cells specific for immunodominant epitopes derived from three different chronic viruses (i.e., CMV, EBV, and HIV-1), presented by commonly expressed HLA (i.e., A2, B7, and B57)

Summary

Introduction

A hallmark of human antiviral T cells is their ability to recognize viral peptide antigen bound to a self-human leukocyte antigen (HLA) on the surface of infected cells. Whilst this recognition often displays exquisite specificity, it is not uncommon for some of these T cells to cross-react with closely related peptide-HLA (pHLA) complexes, such as a peptide from a different viral strain [1]. These forms of heterologous immunity, otherwise known as T cell cross-reactivity, are not beneficial to the host and can lead to transplant rejection, drug hypersensitivity and autoimmunity, respectively. Cross-reactivity is an intrinsic feature of T cells, necessitated by the limited availability of unique human T cell receptor (TCR) clonotypes (1015 pHLA combinations) [7]

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Conclusion