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Protective HIV-specific CD8+ T cells evade Treg cell suppression

Nature Medicine volume 17, pages 989–995 (2011)Cite this article

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A Corrigendum to this article was published on 07 September 2011

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Abstract

Specific human leukocyte antigens (HLAs), notably HLA-B*27 and HLA-B*57 allele groups, have long been associated with control of HIV-1. Although the majority of HIV-specific CD8+ T cells lose proliferative capacity during chronic infection, T cells restricted by HLA-B*27 or HLA-B*57 allele groups do not. Here we show that CD8+ T cells restricted by 'protective' HLA allele groups are not suppressed by Treg cells, whereas, within the same individual, T cells restricted by 'nonprotective' alleles are highly suppressed ex vivo. This differential sensitivity of HIV-specific CD8+ T cells to Treg cell–mediated suppression correlates with their expression of the inhibitory receptor T cell immunoglobulin domain and mucin domain 3 (Tim-3) after stimulation with their cognate epitopes. Furthermore, we show that HLA-B*27– and HLA-B*57–restricted effectors also evade Treg cell–mediated suppression by directly killing Treg cells they encounter in a granzyme B (GzmB)-dependent manner. This study uncovers a previously unknown explanation for why HLA-B*27 and HLA-B*57 allele groups are associated with delayed HIV-1 disease progression.

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Figure 1: Treg cell suppression of in vitro proliferative ability or cytokine secretion of CD8+ T cells restricted by HLA-B*57, HLA-B*27, HLA-A*03 and control HLAs (HLA-A*02, HLA-A*24 and HLA-B*08).
Figure 2: Frequency of CD8+Tim-3+ T cells following stimulation with their cognate epitopes.
Figure 3: CFSE dilution data showing inhibition of Gal-9–Tim-3 interactions by lactose and siRNA.
Figure 4: CFSE dilution data showing CD8+ T cells restricted by HLA-B*57 and HLA-B*27 resist Treg cell-mediated suppression in a GzmB dependent manner.
Figure 5: CD8+ T cells restricted by HLA-B*27 and HLA-B*57 induce Treg apoptosis in a GzmB-dependent manner.
Figure 6: Model depicting how HLA-B*27– or HLA-B*57–restricted HIV-specific CD8+ T cells evade Treg cell suppression and subsequently control HIV replication.

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  • 07 September 2011

     In the version of this article initially published, Figure 3c and Figure 3d were switched. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank our study volunteers for providing samples and supporting this work, as well as the clinical staff for their dedication to this research. This work was supported by US National Institutes of Health (NIH) grants R01 AI65328, R21 AI089373, U01 AI4674, U01 AI 46725, P01 AI57005, P30 AI27757, a New Investigator Award (for S.E.) from the University of Washington/Fred Hutchinson Cancer Research Center Center for AIDS Research (CFAR), AI30731, AI 081060, R37 AI042528 and M01-RR-00037 (the University of Washington General Clinical Research Center). This research was supported by the University of Washington Center for AIDS Research (CFAR), an NIH funded program (P30 AI027757) which is supported by the NIH National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of Child Health and Human Development, National Heart, Lung, and Blood Institute and National Center for Complementary and Alternative Medicine). We also acknowledge the support of the James. B. Pendleton Charitable Trust.

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Authors and Affiliations

  1. Viral Vaccine Program, Seattle Biomedical Research Institute (Seattle Biomed), Seattle, Washington, USA

    Shokrollah Elahi, Warren L Dinges, Nicholas Lejarcegui & Helen Horton

  2. Polyclinic Infectious Disease, Seattle, Washington, USA

    Warren L Dinges

  3. Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Kerry J Laing, David M Koelle & M Juliana McElrath

  4. Department of Medicine, University of Washington, Seattle, Washington, USA

    Ann C Collier, David M Koelle, M Juliana McElrath & Helen Horton

  5. Department of Global Health Medicine, University of Washington, Seattle, Washington, USA

    David M Koelle, M Juliana McElrath & Helen Horton

  6. Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA

    David M Koelle & M Juliana McElrath

  7. Benaroya Research Institute, Seattle, Washington, USA

    David M Koelle

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Contributions

S.E. designed and performed all the experiments and wrote part of the manuscript. N.L. assisted S.E. to perform some of the experiments. W.L.D. performed statistical analysis and graphing design. K.J.L. performed epitope mapping for individuals infected with HSV. D.M.K. advised on the HSV experiment. D.M.K., K.J.L., M.J.M. and A.C.C. supplied samples from subjects. H.H. designed and supervised all of the research and wrote the manuscript. All authors revised and edited the manuscript.

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Correspondence to Helen Horton.

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The authors declare no competing financial interests.

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Elahi, S., Dinges, W., Lejarcegui, N. et al. Protective HIV-specific CD8+ T cells evade Treg cell suppression. Nat Med 17, 989–995 (2011). https://doi.org/10.1038/nm.2422

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