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. 2011 Jul 17;17(8):989-95.
doi: 10.1038/nm.2422.

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

Shokrollah Elahi  1 , Warren L Dinges, Nicholas Lejarcegui, Kerry J Laing, Ann C Collier, David M Koelle, M Juliana McElrath, Helen Horton
Affiliations

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

Shokrollah Elahi et al. Nat Med. .

Erratum in

  • Nat Med. 2011 Sep;17(9):1153

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 T(reg) 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 T(reg) 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 T(reg) cell-mediated suppression by directly killing T(reg) 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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Figures

Figure 1
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). (a) Background-subtracted percentage CFSEloCD8+ T cells in PBMCs with or without Treg cells when cultured in the presence of HIV-1 epitopes recognized by CD8+ T cells restricted by various HLA alleles. (b) Background-subtracted HIV-specific IFN-γ ELISPOT responses in the presence and absence of Treg cells. HLA-B*27 or HLA-B*57–restricted and non–HLA-B*27– and HLA-B*57–restricted responses are shown after stimulation with their cognate epitopes. SFC, spot-forming cell. In a and b, Wilcoxon signed-rank (WSR) test was used. (c) Percentage suppression of proliferation grouped according to HLA restricting allele. (d) Percentage suppression of cytokine secretion grouped according to HLA restricting allele. In c and d, Kruskal-Wallis (KW) test was used for grouped comparisons with a post hoc Dunn’s test showing significant subgroup comparisons with horizontal lines. (e) Differential suppression of proliferation of HLA-B*27– and HLA-B*57– versus HLA-A*03– and control HLA–restricted HIV-specific CD8+ CTLs within the same person. NP02 and NP41 are two LTNPs. (f) Percentage suppression of proliferation by Treg cells of HLA-B*57–restricted CD8+ CTLs in HLAB*57+ LTNP versus HLA-B*57+ delayed progressors (DP). (g) Longitudinal analyses of percentage suppression of proliferation by Treg cells of HLA-B*57–restricted CD8+ CTLs before and after progression in HLA-B*57+ individuals.
Figure 2
Figure 2
Frequency of CD8+Tim-3+ T cells following stimulation with their cognate epitopes. (a) Percentage of Tim-3+ CD8+ T cells using allophycocyanin-labeled HLA-A*03–RLRPGGKKK tetramer or phycoerythrin-labeled HLA-B*57-TSTLQEQIGW tetramer staining of PBMCs before and after stimulation with their cognate epitopes. Top right quadrant shows percentage of Tim-3+tetramer+ CD8+ CTLs. (b) Percentage of Tim-3+ on CD8+ T cells using CD137 to identify antigen-specific T cells after stimulation with their cognate epitopes. (c) Percentage of CD137+Tim-3+ T cells after stimulation of PBMCs from different individuals with their corresponding epitopes.
Figure 3
Figure 3
CFSE dilution data showing inhibition of Gal-9–Tim-3 interactions by lactose and siRNA. (a) Examples of proliferation of PBMCs stimulated with their corresponding epitopes, showing percentage CFSEloCD8+ T cells in the absence or presence of lactose. (b) Examples of proliferation of CFSE-labeled, Treg cell–depleted PBMCs stimulated with their cognate epitopes in the presence of Treg cells treated with either LGALS9 siRNA or siControl (at 1:0.25 ratio). The measures of coculture suppression by Treg cells in the presence or absence of lactose or siRNA are shown for a representative experiment from three repeat experiments for each approach. (c) Percentage of Treg cell suppression calculated after stimulation of CD8+ T cells with their corresponding epitopes in the presence of lactose. (d) Percentage of Treg cell suppression calculated after stimulation of CD8+ T cells with their cognate epitopes in the presence of LGALS9 siRNA–treated Treg cells (at 1:0.25 ratio).
Figure 4
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. (a) Percentage CFSEloCD8+ T cells after CFSE-labeled isolated CD8+ T cells were stimulated with their corresponding epitopes alone or together with Treg cells (at 1:0.25 ratio), and also in the presence or absence of a GzmB peptide inhibitor (z-AAD-CMK). Examples of flow data are shown in Supplementary Figure 3a. (b) Percentage CFSEloCD8+ T cells after electroporation with GZMB siRNA or nonhybridizing negative control (siControl) siRNA oligonucleotides and stimulation with their cognate epitopes alone or with Treg cells (at 1:0.25 ratio). Examples of flow data are shown in Supplementary Figure 3b.
Figure 5
Figure 5
CD8+ T cells restricted by HLA-B*27 and HLA-B*57 induce Treg apoptosis in a GzmB-dependent manner. (a–c) Percentage annexin V+ Treg cells (CD3+CD4+CD25hiCD127lo) in PBMCs stimulated for 4 d (a), 24 h (b) or 24–72 h (c) with HLA-B*27–, HLA-B*57–, HLA-B*39– or HLA-A*03–restricted epitopes in the presence or absence of GzmB peptide inhibitor. These data are representative of three separate experiments from different LTNPs. (d) Percentage annexin V+ Treg cells in PBMCs stimulated with HLA-B*57–restricted epitopes from HLA-B*57+ LTNP versus HLA-B*57+ DPs. (e,f) Percentage annexin V+ Treg cells in PBMCs stimulated with HLA-B*57–restricted epitopes before and after progression to disease. (g) Treg cell frequencies in HIV-1–seronegative individuals versus HIV-1 infected HLA-B*27+ or HLA-B*57+ and HLA-B*27− or HLA-B*57− LTNPs. Percentages of CD4+CD25hiFOXP3+ Treg cells are shown in PBMCs from 12 HIV-seronegative HLA-B*27+ or HLA-B*57+ individuals, 12 HLA-B*27– or HLA-B*-57– individuals, 13 HLA-B*27+ or HLA-B*57+ LTNPs and 8 HLA-B*27− or HLA-B*57− LTNPs.
Figure 6
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. HIV-specific, HLA-B*27–restricted CD8+ T cells do not upregulate surface expression of Tim-3 upon recognition of their cognate epitopes on HIV-infected CD4+ T cells, whereas HIV-specific, HLA-A*03–restricted CD8+ T cells upregulate high surface expression of Tim-3. Treg cells suppress HLA-A*03–restricted CD8+ T cells owing to their high expression of Tim-3 but cannot suppress proliferation of HLA-B*27–restricted CD8+ T cells. Highly proliferating HLA-B*27–restricted CD8+ T cells upregulate high levels of GzmB and kill not only infected CD4+ T cells but also infected Treg cells that they encounter. Thus, HLA-B*27–restricted CD8+ T cells can control HIV replication during chronic infection, whereas HLA-A*03–restricted CD8+ T cells cannot.
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