HLA-E–restricted HIV-1–specific CD8+ T cell responses in natural infection
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
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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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 4

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

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Ex vivo detection of KL9- and KF11-specific CD8+ T cell responses restri...
Positive isolated CD8+ T cells from PBMCs were cultured with target cells pulsed with 10 μg/mL peptide without long-term expansion. (A) Comparison between KF11- and KL9-induced IFN-γ response using ex vivo ELISPOT (n = 9). The dashed line represents the positive cutoff value of 55 SFU/106 PBMCs. (B and C) Net frequency of production of cytokine/effector molecules by CD8+ T cells responding to KF11/KL9 presentation by HLA-B*57 using the K562.B*57 cell line as APCs (B); and functional score (FS) and polyfunctional score (PFS) (C) (n = 8). Net frequency was calculated by subtraction of the no-peptide-pulse control of the identical APCs. (D) Comparison of responder rates between KF11-induced (n = 9) and KL9-induced (n = 8) CD8+ T cell response using HLA-E–expressing AEH cell line as APCs. (E and F) Data similar to those in B and C but for HLA-E–restricted responses: net frequency of production of cytokine/effector molecules (E); and functional score and polyfunctional score (F) (n = 8). Error bars represent mean ± SEM. Wilcoxon matched-pairs signed rank test was used in A–C, E, and F, and Fisher’s exact test in D, to determine statistical significance.