Empty conformers of HLA-B preferentially bind CD8 and regulate CD8+ T cell function.

Jie Geng,Malini Raghavan,John D Altman,Sujatha Krishnakumar

doi:10.7554/elife.36341

Jie Geng, Malini Raghavan + Show 2 more

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https://doi.org/10.7554/elife.36341

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Abstract

When complexed with antigenic peptides, human leukocyte antigen (HLA) class I (HLA-I) molecules initiate CD8+ T cell responses via interaction with the T cell receptor (TCR) and co-receptor CD8. Peptides are generally critical for the stable cell surface expression of HLA-I molecules. However, for HLA-I alleles such as HLA-B*35:01, peptide-deficient (empty) heterodimers are thermostable and detectable on the cell surface. Additionally, peptide-deficient HLA-B*35:01 tetramers preferentially bind CD8 and to a majority of blood-derived CD8+ T cells via a CD8-dependent binding mode. Further functional studies reveal that peptide-deficient conformers of HLA-B*35:01 do not directly activate CD8+ T cells, but accumulate at the immunological synapse in antigen-induced responses, and enhance cognate peptide-induced cell adhesion and CD8+ T cell activation. Together, these findings indicate that HLA-I peptide occupancy influences CD8 binding affinity, and reveal a new set of regulators of CD8+ T cell activation, mediated by the binding of empty HLA-I to CD8.

Highlights

The major histocompatibility complex class I (MHC-I) molecules play a crucial role in adaptive immune responses by presenting antigenic peptides to CD8+ T cells, which enables the immune system to detect transformed or infected cells that display peptides from foreign or mutated self-proteins
The NIH tetramer core facility has developed HLA-I molecules with epitope-linked b2m (ELBM), wherein an HLA-I binding peptide is covalently linked to human b2m via a linker peptide that contains a protease cleavage site
HLA-I heavy chain and b2m are further tethered via leucine zippers (LZ) at their C-termini (Figure 1A)

Summary

Introduction

The major histocompatibility complex class I (MHC-I) molecules play a crucial role in adaptive immune responses by presenting antigenic peptides to CD8+ T cells, which enables the immune system to detect transformed or infected cells that display peptides from foreign or mutated self-proteins. Peptides are an integral component of MHC-I molecules. In the MHC-I antigen presentation process, peptides are mainly produced in the cytosol by proteasome and translocated to the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). There are several quality control components to ensure that most cell surface MHC-I molecules are filled with optimal peptide. Under certain pathophysiological conditions, MHC-I peptide-deficient or open conformers are detected on the cell surface. Prior evidence suggests that peptide-deficient conformers of MHC-I molecules appear on the cell surface of activated lymphoid cells (Madrigal et al, 1991; Schnabl et al, 1990), TAP-deficient cells (Ljunggren et al, 1990; Ortiz-Navarrete and Hammerling, 1991) or EBV transformed B cells (Madrigal et al, 1991)

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