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. 2021 May 27;5(5):360-369.
doi: 10.4049/immunohorizons.2100026.

Diverse Mucosal-Associated Invariant TCR Usage in HIV Infection

Shubhanshi Trivedi  1 , Taliman Afroz  2 , Michael S Bennett  2 , Kendal Angell  2 , Fabio Barros  2 , Racheal A Nell  2 , Jian Ying  2 , Adam M Spivak  2   3 , Daniel T Leung  1   3
Affiliations

Diverse Mucosal-Associated Invariant TCR Usage in HIV Infection

Shubhanshi Trivedi et al. Immunohorizons. .

Abstract

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that specifically target bacterial metabolites but are also identified as innate-like sensors of viral infection. Individuals with chronic HIV-1 infection have lower numbers of circulating MAIT cells compared with healthy individuals, yet the features of the MAIT TCR repertoire are not well known. We isolated and stimulated human PBMCs from healthy non-HIV-infected donors (HD), HIV-infected progressors on antiretroviral therapy, and HIV-infected elite controllers (EC). We sorted MAIT cells using flow cytometry and used a high-throughput sequencing method with bar coding to link the expression of TCRα, TCRβ, and functional genes of interest at the single-cell level. We show differential patterns of MAIT TCR usage among the groups. We observed expansions of certain dominant MAIT clones in HIV-infected individuals upon Escherichia coli stimulation, which was not observed in clones of HD. We also found different patterns of CDR3 amino acid distributions among the three groups. Furthermore, we found blunted expression of phenotypic genes in HIV individuals; most notably, HD mounted a robust IFNG response to stimulation, whereas both HIV-infected progressors and EC did not. In conclusion, our study describes the diverse MAIT TCR repertoire of persons with chronic HIV-1 infection and suggest that MAIT clones of HIV-infected persons may be primed for expansion more than that of noninfected persons. Further studies are needed to examine the functional significance of unique MAIT cell TCR usage in EC.

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Conflict of interest statement

DISCLOSURES

The authors have no financial conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.. TCR usage in MAIT cells is different in HIV infection.
MAIT cells were sorted from unstimulated and E. coli–stimulated PBMCs from four HD, four PR on ART, and three HIV-infected EC, and TCR was analyzed at the single-cell level using Illumina MiSeq sequencing. (A) Pie charts showing percentage frequency of unexpanded and expanded MAIT cell clones in each group. (B) TCR usage in unstimulated and in vitro–stimulated expanded MAIT cell clones obtained from pooling HD, PR, and EC individuals is shown as heatmap with hierarchical clustering performed using Euclidean distance. (C) TRAJ usage, (D) TRBV usage, and (E) TRBJ usage in all three groups is shown as heatmap.
FIGURE 2.
FIGURE 2.. MAIT CDR3 region displays length and sequence diversity in HIV infection.
The length distribution of CDR3α and CDR3β sequences from all donors in each group was analyzed. (A) Graphs depict CDR3α and CDR3β lengths observed in HD (black circle), PR (red squares), and EC (blue triangle) groups. Each symbol represents individual donor. (B) Visual representation of amino acid enrichments at each position across the CDR3α core compiled from expanded MAIT cell clones in each group. Entropy for distribution of amino acid at each of the 10 sites of HD, PR, and EC groups before and after stimulation was calculated, as described previously (38). (C) Visual representation of amino acid enrichments at each position and Shannon entropy analysis across the CDR3β core compiled from expanded MAIT cell clones in each group. CDR3α and CDR3β sequences from all donors in each group were pooled, and analysis was confined to sequences with a length of 10 aa. Graphics were generated using Seq2Logo. (D and E) CDR3α and CDR3β sequence similarity between each pair of subjects in a group (intragroup: HD versus HD, PR versus PR, and EC versus EC) and between each group (intragroup: HD versus EC, EC versus HIV, and HD versus HIV) before and after stimulation, as described previously (W.-J. Shen et al., manuscript posted on arXiv, 1205.6031).
FIGURE 3.
FIGURE 3.. MAIT cell phenotype is different in HIV infection.
MAIT cell TCRα and TCRβ genes and functional genes of interest were simultaneously sequenced. Bar graphs represent percentage of all the dominant MAIT cell clones expressing (A) IFNG, (B) TNFA, (C) GZMB, (D) PRF1, (E) TBET, (F) GATA3, (G) RORC, (H) BCL6, (I) RUNX1, and (J) RUNX3 genes in HD, HIV, and EC. Data were analyzed using two-way ANOVA with Tukey multiple comparisons test.
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References

    1. Nicolosi A, Corrêa Leite ML, Musicco M, Arici C, Gavazzeni G, Lazzarin A, and Italian Study Group on HIV Heterosexual Transmission. 1994. The efficiency of male-to-female and female-to-male sexual transmission of the human immunodeficiency virus: a study of 730 stable couples. Epidemiology 5: 570–575. - PubMed
    1. Reis Machado J, da Silva MV, Cavellani CL, dos Reis MA, Monteiro MLGR, Teixeira VP, and Miranda Corrêa RR. 2014. Mucosal immunity in the female genital tract, HIV/AIDS. BioMed Res. Int 2014: 350195. - PMC - PubMed
    1. Stieh DJ, Maric D, Kelley ZL, Anderson MR, Hattaway HZ, Beilfuss BA, Rothwangl KB, Veazey RS, and Hope TJ. 2014. Vaginal challenge with an SIV-based dual reporter system reveals that infection can occur throughout the upper and lower female reproductive tract. PLoS Pathog. 10: e1004440. - PMC - PubMed
    1. Belyakov IM, and Berzofsky JA. 2004. Immunobiology of mucosal HIV infection and the basis for development of a new generation of mucosal AIDS vaccines. Immunity 20: 247–253. - PubMed
    1. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase AT, and Douek DC. 2004. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J. Exp. Med 200: 749–759. - PMC - PubMed

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