title: Protective HIV-specific CD8+ T cells evade Treg cell suppression.
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.
authors.affiliation: Viral Vaccine Program, Seattle Biomedical Research Institute (Seattle Biomed), Seattle, Washington, USA.
authors.forename: Shokrollah
authors.initials: S
authors.lastname: Elahi
authors.forename: Warren L
authors.initials: WL
authors.lastname: Dinges
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lejarcegui
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Laing
authors.forename: Ann C
authors.initials: AC
authors.lastname: Collier
authors.forename: David M
authors.initials: DM
authors.lastname: Koelle
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.forename: Helen
authors.initials: H
authors.lastname: Horton
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016923:Cell Death / Q000276:immunology; D018604:Epitope Mapping; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000821:virology*
chemical_list: C448908:HAVCR2 protein, human; D015235:HLA-B Antigens; D015796:HLA-B27 Antigen; C103707:HLA-B57 antigen; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D034741:RNA, Small Interfering