Interrogating the recognition landscape of a conserved HIV-specific TCR reveals distinct bacterial peptide cross-reactivity.

Juan L Mendoza,K Christopher Garcia,Andrew J Mcmichael,Lilian H Lam,Marvin H Gee,Suzanne Fischer,Simon Brackenridge,Michael Birnbaum,Fiona M Powrie,Geraldine M Gillespie

doi:10.7554/elife.58128

Juan L Mendoza, K Christopher Garcia + Show 8 more

Open Access

https://doi.org/10.7554/elife.58128

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Abstract

T cell cross-reactivity ensures that diverse pathogen-derived epitopes encountered during a lifetime are recognized by the available TCR repertoire. A feature of cross-reactivity where previous exposure to one microbe can alter immunity to subsequent, non-related pathogens has been mainly explored for viruses. Yet cross-reactivity to additional microbes is important to consider, especially in HIV infection where gut-intestinal barrier dysfunction could facilitate T cell exposure to commensal/pathogenic microbes. Here we evaluated the cross-reactivity of a 'public', HIV-specific, CD8 T cell-derived TCR (AGA1 TCR) using MHC class I yeast display technology. Via screening of MHC-restricted libraries comprising ~2×108 sequence-diverse peptides, AGA1 TCR specificity was mapped to a central peptide di-motif. Using the top TCR-enriched library peptides to probe the non-redundant protein database, bacterial peptides that elicited functional responses by AGA1-expressing T cells were identified. The possibility that in context-specific settings, MHC class I proteins presenting microbial peptides influence virus-specific T cell populations in vivo is discussed.

Highlights

Cross-reactivity represents an intrinsic feature of immunity that allows post-thymically selected T cell receptors (TCRs) to recognize distinct peptides originating from diverse microbial origins when bound by a single MHC
Yeast cell libraries displaying HLA-B*57:03-b2m linked to a randomized peptide library were generated to screen the breadth of AGA1 TCR binding (see Figure 1A (i) for overview of strategy)
A myc-tag incorporated between the MHC a3 domain and the Aga2 yeast protein allows the monitoring of peptide-b2m-HLA-B*57:03 expression on the yeast cell surface (Figure 1A (ii))

Summary

Introduction

Cross-reactivity represents an intrinsic feature of immunity that allows post-thymically selected T cell receptors (TCRs) to recognize distinct peptides originating from diverse microbial origins when bound by a single MHC. The possibility that cross-reactive T cells could influence immunity to non-related pathogens exists but has not been extensively explored – this is relevant in the setting of HIV infection, where viral-induced gut-intestinal (GI) barrier dysbiosis could potentially allow commensal or pathogenic microbes to influence virus-specific T cell populations. This has been addressed to some extent in the context of HIV infection for MHC class II and CD4 T cells (Su et al, 2013; Campion et al, 2014), this topic has received only limited attention in relation to CD8+ T cells and MHC class I restricted epitopes (Pohlmeyer et al, 2018).

Results

Discussion

Materials and methods

Funding Funder Medical Research Council