HLA-G-mediated inhibition of antigen-specific cytotoxic T lymphocytes

Abstract

In the present study, we demonstrate that the non-classical MHC class I molecule HLA-G impairs specific cytolytic T cell functions in addition to its well-established inhibition of NK lysis. The antigen-specific cytotoxic T lymphocyte (CTL) response analyzed was mediated by CD8(+) T cells specific for the influenza virus matrix epitope, M58-66, presented by HLA-A2. The transfection of HLA-G1 cDNA in target cells carrying the M58-66 epitope reduced their lysis by these virus-specific CTL. This HLA-G-mediated inhibition of antigen-specific CTL lysis was (i) peptide dose dependent, (ii) reversed by blocking HLA-G with a specific mAb and (iii) still observed despite the blockade of HLA-E/CD94/NKG2A interaction. By inhibiting both CTL and NK functions, HLA-G appears to have an extensive role in immune tolerance.

HLA-G2, -G3, and -G4 Isoforms Expressed as Nonmature Cell Surface Glycoproteins Inhibit NK and Antigen-Specific CTL Cytolysis

“…All transfectants were controlled by RT-PCR and Southern blot analysis using specific primers and probes (25). The NK-like YT2C2-PR subclone and the M58 -66 influenza virus matrix peptide-specific CTL line (HC12) were obtained as previously described (21,26). Cells were maintained in RPMI 1640 medium supplemented with 10% inactivated FCS, 2 mM L-glutamine, 1 g/ml gentamicin, and fungizone.…”

“…Previous data have shown that the full-length HLA-G1 isoform impairs the lytic activities of both NK and CTL cytotoxic effectors (21,28). To determine whether the truncated HLA-G isoforms, like HLA-G1, were functional molecules with respect to CTL and NK effectors, we conducted chromium release assays using M8 transfected cells as targets.…”

“…First identified on extravillous cytotrophoblasts (6,7), HLA-G is also expressed in HLA class I-positive tissues such as oocytes (8), embryos (9), amnion (10), thymic epithelial cells (11), cytokineactivated monocytes (12,13), and some tumors (14). HLA-G1 has been identified as a key molecule in maternal-fetal tolerance (15), since it inhibits the lytic activity of both decidual and peripheral blood NK cells (16 -20) as well as Ag-specific CTL (21) and allogeneic proliferative responses (22). Additional evidence that HLA-G can be expressed in heart after transplantation suggests that it may participate in graft tolerance (23).…”

Production of sHLA-G molecules by in vitro matured cumulus-oocyte complex

“…HLA-G molecules inhibit, together with HLA-C and -E, the innate natural killer response against cytotrophoblast cells which lack classical HLA class I and II expression (3)(4)(5). HLA-G antigens affect the adaptative cellular response inducing the apoptosis of cytotoxic CD8 + T lymphocytes (6,7), impairing CD4 + T cell functions and preventing dendritic cell maturation (8,9). HLA-G molecules also induce immunosuppressive regulatory T cell development (10,11).…”

Annexin V Incorporated into Influenza Virus Particles Inhibits Gamma Interferon Signaling and Promotes Viral Replication

“…Important factors in the pathogenesis of influenza include the efficient replication of the virus in the respiratory tract and the host immune response, traits that are dependent on each other (4)(5)(6). While the immune response aims to control the spread of the virus, IAV has developed strategies for subverting host defenses, thereby facilitating their spread (7)(8)(9)(10). Further knowledge into how IAV escapes the host immunosurveillance is critical for the design of new treatments that are able to control the disease.…”