Identifying a Minor Histocompatibility Antigen in Mauritian Cynomolgus Macaques Encoded by APOBEC3C.

Jason T Weinfurter,Matthew R Reynolds,Roger W Wiseman,Michael E Graham,Adam J Ericsen,David A Price,Sian Llewellyn-Lacey,Lea M Matschke

doi:10.3389/fimmu.2020.586251

Abstract

Allogeneic hematopoietic stem cell transplants can lead to dramatic reductions in human immunodeficiency virus (HIV) reservoirs. This effect is partially mediated by donor T cells recognizing lymphocyte-expressed minor histocompatibility antigens (mHAgs). The potential to mark malignant and latently infected cells for destruction makes mHAgs attractive targets for cellular immunotherapies. However, testing such HIV reservoir reduction strategies will likely require preclinical studies in non-human primates (NHPs). In this study, we used a combination of alloimmunization, whole exome sequencing, and bioinformatics to identify an mHAg in Mauritian cynomolgus macaques (MCMs). We mapped the minimal optimal epitope to a 10-mer peptide (SW10) in apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3C (APOBEC3C) and determined the major histocompatibility complex class I restriction element as Mafa-A1∗063, which is expressed in almost 90% of MCMs. APOBEC3C SW10-specific CD8+ T cells recognized immortalized B cells but not fibroblasts from an mHAg-positive MCM. These results provide a framework for identifying mHAgs in a non-transplant setting and suggest that APOBEC3C SW10 could be used as a model antigen to test mHAg-targeted therapies in NHPs.

Highlights

The establishment of long-lived viral reservoirs is a major obstacle to developing curative therapies for human immunodeficiency virus (HIV) [1,2,3,4]
We identified 21 Mauritian cynomolgus macaques (MCMs) heterozygous for the M1 and M2 major histocompatibility complex (MHC) haplotypes (M1/M2). minor histocompatibility antigens (mHAgs)-reactive T cells were stimulated in vivo by alloimmunizing four M1/M2 MCMs with a mixture of Peripheral blood mononuclear cells (PBMCs) from four MHC-identical MCMs
APOBEC3 genes are expressed widely in immune cells [37, 42, 43]. In line with these gene expression studies, we found that APOBEC3C SW10-specific T cells recognized B lymphoblastoid cells (BLCs) but not fibroblasts isolated from an mHAgpos MCM

Summary

Introduction

The establishment of long-lived viral reservoirs is a major obstacle to developing curative therapies for human immunodeficiency virus (HIV) [1,2,3,4]. These latent reservoirs are unaffected by antiretroviral therapy (ART) and readily reactivate upon cessation of treatment [5, 6]. It has been estimated that over 60 years of continuous ART would be needed to decay latently infected cells to extinction [2, 7]. Human immunodeficiency virus-infected patients who develop hematological malignancies are commonly treated with allogeneic hematopoietic stem cell transplants (allo-HSCTs), which frequently lead to dramatic decreases in latent viral reservoirs.

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Conclusion