HIV-1 Tat protein induces PD-L1 (B7-H1) expression on dendritic cells through tumor necrosis factor alpha- and toll-like receptor 4-mediated mechanisms.
Chronic human immunodeficiency virus type 1 (HIV-1) infection is associated with induction of T-cell coinhibitory pathways. However, the mechanisms by which HIV-1 induces upregulation of coinhibitory molecules remain to be fully elucidated. The aim of the present study was to determine whether and how HIV-1 Tat protein, an immunosuppressive viral factor, induces the PD-1/PD-L1 coinhibitory pathway on human dendritic cells (DCs). We found that treatment of DCs with whole HIV-1 Tat protein significantly upregulated the level of expression of PD-L1. This PD-L1 upregulation was observed in monocyte-derived dendritic cells (MoDCs) obtained from either uninfected or HIV-1-infected patients as well as in primary myeloid DCs from HIV-negative donors. In contrast, no effect on the expression of PD-L2 or PD-1 molecules was detected. The induction of PD-L1 on MoDCs by HIV-1 Tat (i) occurred in dose- and time-dependent manners, (ii) was mediated by the N-terminal 1-45 fragment of Tat, (iii) did not require direct cell-cell contact but appeared rather to be mediated by soluble factor(s), (iv) was abrogated following neutralization of tumor necrosis factor alpha (TNF-α) or blocking of Toll-like receptor 4 (TLR4), (v) was absent in TLR4-knockoout (KO) mice but could be restored following incubation with Tat-conditioned medium from wild-type DCs, (vi) impaired the capacity of MoDCs to functionally stimulate T cells, and (vii) was not reversed functionally following PD-1/PD-L1 pathway blockade, suggesting the implication of other Tat-mediated coinhibitory pathways. Our results demonstrate that HIV-1 Tat protein upregulates PD-L1 expression on MoDCs through TNF-α- and TLR4-mediated mechanisms, functionally compromising the ability of DCs to stimulate T cells. The findings offer a novel potential molecular target for the development of an anti-HIV-1 treatment.


OBJECTIVE
The objective of this study was to investigate the effect of human immunodeficiency virus type 1 (HIV-1) Tat on the PD-1/PD-L1 coinhibitory pathway on human monocyte-derived dendritic cells (MoDCs). We found that treatment of MoDCs from either healthy or HIV-1-infected patients with HIV-1 Tat protein stimulated the expression of PD-L1. We demonstrate that this stimulation was mediated through an indirect mechanism, involving tumor necrosis factor alpha (TNF-α) and Toll-like receptor 4 (TLR4) pathways, and resulted in compromised ability of Tat-treated MoDCs to functionally stimulate T-cell proliferation.
INSERM, U1043, Toulouse, France CNRS, U5282, Toulouse, France Université Paul Sabatier Toulouse, Toulouse, France.
Rémi
R
Planès
Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.
Lbachir
L
BenMohamed
INSERM, U1043, Toulouse, France CNRS, U5282, Toulouse, France Université Paul Sabatier Toulouse, Toulouse, France.
Kaoutar
K
Leghmari
INSERM, U1043, Toulouse, France CNRS, U5282, Toulouse, France Université Paul Sabatier Toulouse, Toulouse, France Department of Infectious Diseases, Toulouse University Hospital, Toulouse, France.
Pierre
P
Delobel
INSERM, U1043, Toulouse, France CNRS, U5282, Toulouse, France Université Paul Sabatier Toulouse, Toulouse, France Department of Virology, CHU Purpan, Toulouse, France.
Jacques
J
Izopet
INSERM, U1043, Toulouse, France CNRS, U5282, Toulouse, France Université Paul Sabatier Toulouse, Toulouse, France bahraoui@cict.fr.
Elmostafa
E
Bahraoui
D020816:Amino Acid Motifs; D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics* / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000821:virology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
D060890:B7-H1 Antigen; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus