Subset- and Antigen-Specific Effects of Treg on CD8+ T Cell Responses in Chronic HIV Infection.
We, and others, have reported that in the HIV-negative settings, regulatory CD4+CD25highFoxP3+ T cells (Treg) exert differential effects on CD8 subsets, and maintain the memory / effector CD8+ T cells balance, at least in part through the PD-1/PD-L1 pathway. Here we investigated Treg-mediated effects on CD8 responses in chronic HIV infection. As compared to Treg from HIV negative controls (Treg/HIV-), we show that Treg from HIV infected patients (Treg/HIV+) did not significantly inhibit polyclonal autologous CD8+ T cell function indicating either a defect in the suppressive capacity of Treg/HIV+ or a lack of sensitivity of effector T cells in HIV infection. Results showed that Treg/HIV+ inhibited significantly the IFN-γ expression of autologous CD8+ T cells stimulated with recall CMV/EBV/Flu (CEF) antigens, but did not inhibit HIV-Gag-specific CD8+ T cells. In cross-over cultures, we show that Treg/HIV- inhibited significantly the differentiation of either CEF- or Gag-specific CD8+ T cells from HIV infected patients. The expression of PD-1 and PD-L1 was higher on Gag-specific CD8+ T cells as compared to CEF-specific CD8+ T cells, and the expression of these markers did not change significantly after Treg depletion or co-culture with Treg/HIV-, unlike on CEF-specific CD8+ T cells. In summary, we show a defect of Treg/HIV+ in modulating both the differentiation and the expression of PD-1/PD-L1 molecules on HIV-specific CD8 T cells. Our results strongly suggest that this particular defect of Treg might contribute to the exhaustion of HIV-specific T cell responses.
INSERM, U955, Créteil, France.|Immunology Department, National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria.
Maria
M
Nikolova
INSERM, U955, Créteil, France.|Université Paris Est Créteil, Faculté de Médecine, Créteil, France.|Vaccine Research Institute, Créteil, France.
Aurélie
A
Wiedemann
Immunology Department, National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria.
Maria
http://orcid.org/0000-0001-9570-9896
M
Muhtarova
Immunology Department, National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria.
Daniela
D
Achkova
INSERM, U955, Créteil, France.|Université Paris Est Créteil, Faculté de Médecine, Créteil, France.|Vaccine Research Institute, Créteil, France.
Christine
C
Lacabaratz
INSERM, U955, Créteil, France.|Université Paris Est Créteil, Faculté de Médecine, Créteil, France.|Vaccine Research Institute, Créteil, France.|AP-HP, Groupe Henri-Mondor Albert-Chenevier, Immunologie clinique, Créteil, France.
Yves
Y
Lévy
D017209:Apoptosis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D018920:Coculture Techniques; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*