HLA-E–restricted HIV-1–specific CD8+ T cell responses in natural infection
Anju Bansal, … , June Kan-Mitchell, Paul A. Goepfert
Anju Bansal, … , June Kan-Mitchell, Paul A. Goepfert
Published July 6, 2021
Citation Information: J Clin Invest. 2021;131(16):e148979. https://doi.org/10.1172/JCI148979.
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Research Article Infectious disease

HLA-E–restricted HIV-1–specific CD8+ T cell responses in natural infection

Abstract

CD8+ T cell responses restricted by MHC-E, a nonclassical MHC molecule, have been associated with protection in an SIV/rhesus macaque model. The biological relevance of HLA-E–restricted CD8+ T cell responses in HIV infection, however, remains unknown. In this study, CD8+ T cells responding to HIV-1 Gag peptides presented by HLA-E were analyzed. Using in vitro assays, we observed HLA-E–restricted T cell responses to what we believe to be a newly identified subdominant Gag-KL9 as well as a well-described immunodominant Gag-KF11 epitope in T cell lines derived from chronically HIV-infected patients and also primed from healthy donors. Blocking of the HLA-E/KF11 binding by the B7 signal peptide resulted in decreased CD8+ T cell responses. KF11 presented via HLA-E in HIV-infected cells was recognized by antigen-specific CD8+ T cells. Importantly, bulk CD8+ T cells obtained from HIV-infected individuals recognized infected cells via HLA-E presentation. Ex vivo analyses at the epitope level showed a higher responder frequency of HLA-E–restricted responses to KF11 compared with KL9. Taken together, our findings of HLA-E–restricted HIV-specific immune responses offer intriguing and possibly paradigm-shifting insights into factors that contribute to the immunodominance of CD8+ T cell responses in HIV infection.

Authors

Anju Bansal, Mika N. Gehre, Kai Qin, Sarah Sterrett, Ayub Ali, Ying Dang, Sojan Abraham, Margaret C. Costanzo, Leon A. Venegas, Jianming Tang, N. Manjunath, Mark A. Brockman, Otto O. Yang, June Kan-Mitchell, Paul A. Goepfert

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Figure 1

In vitro detection of KL9- and KF11-specific CD8+ T cell responses restricted by HLA-B*57 and HLA-E in chronically HIV-infected individuals.

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In vitro detection of KL9- and KF11-specific CD8+ T cell responses restr...
Positively isolated CD8+ T cells were cultured with KL9- or KF11-pulsed (10 μg/mL) autologous adherent monocytes for 7–12 days. Polyfunctional activation was assessed after 5 hours of stimulation with target cells (221.B*57 or 221.AEH) pulsed with the peptide of interest. No peptide pulse was used as a negative control. 221.B*57 and 221.AEH are antigen-presenting 721.221 cell lines expressing single HLA-B*57:01 and HLA-E*01:01 alleles, respectively. Representative data from 2 HIV-infected individuals are shown in A and B. (A) KL9-specific reactivity restricted by B*57:01 or E*01:01 in patient CHI-7. (B) KF11-specific reactivity restricted by B*57:01 or E*01:01 in patient CHI-6. (C) Summary of KL9- and KF11-specific reactivity in HIV-infected individuals (n = 20) based on CD107a/IFN-γ expression. (D) Net frequency (CD107a/IFN-γ) of paired HLA-E and HLA-B*57 responses specific for KF11 is shown for HIV-infected individuals tested (n = 13) who mounted an HLA-E–restricted CD8+ T cell response. Black and red dots are negative and positive responses, respectively. Error bars represent median value. Wilcoxon matched-pairs signed rank test was used in C and D to determine statistical significance.