ABSTRACT
HLA-B*52:01-C*12:02, which is found in approximately 20% of all Japanese persons, is well known to be associated with ulcerative colitis and Takayasu arteritis. This haplotype is also known to be protective in individuals infected with human immunodeficiency virus (HIV) type 1. Recent studies showed that HLA-B*52:01-restricted HIV-1-specific T cells suppress HIV-1 and that HLA-C*12:02 together with KIR2DL2 play an important role in natural killer cell-mediated control of HIV-1. However, the role of HLA-C*12:02-restricted cytotoxic T lymphocytes (CTLs) in suppressing HIV-1 replication remains unknown. In the present study, we demonstrated that HLA-C*12:02-restricted CTLs specific for 2 immunodominant epitopes, Pol IY11 and Nef MY9, contributed to the suppression of HIV-1 replication in HIV-1-infected individuals. Further analysis demonstrated that these 2 HLA-C*12:02-restricted CTLs together with 4 HLA-B*52:01-restricted ones effectively suppressed HIV-1 in individuals with the HLA-B*52:01-C*12:02 haplotype. Thus, both HLA-C*12:02 and HLA-B*52:01 alleles contribute to HIV-1 suppression via both HIV-1-specific CTLs and natural killer cells in individuals with this haplotype.
Subject(s)
HIV-1/drug effects , HLA-B Antigens/pharmacology , HLA-B52 Antigen/pharmacology , HLA-C Antigens/pharmacology , Haplotypes/immunology , Alleles , Cell Line , Chromium/analysis , Cytokines/analysis , Epitopes, T-Lymphocyte , HIV Infections/diet therapy , HIV Infections/immunology , HIV Infections/virology , HLA-B Antigens/immunology , HLA-B52 Antigen/immunology , HLA-C Antigens/immunology , HLA-C Antigens/isolation & purification , Host-Pathogen Interactions , Humans , Immunodominant Epitopes/pharmacology , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Receptors, KIR2DL2/physiology , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , Virus Replication/drug effects , nef Gene Products, Human Immunodeficiency Virus/immunology , nef Gene Products, Human Immunodeficiency Virus/pharmacology , pol Gene Products, Human Immunodeficiency Virus/immunology , pol Gene Products, Human Immunodeficiency Virus/pharmacologyABSTRACT
Antibody interaction with a specific epitope of the HLA class I alpha1 domain triggers apoptosis of activated but not resting T and B cells by a pathway which involves neither Fas ligand nor tumor necrosis factor-alpha. We have investigated at which stage of activation and proliferation T cells become sensitive to HLA class I-mediated apoptosis, using two monoclonal antibodies (mAb) which recognize the same monomorphic epitope of the HLA class I alpha1 domain (mAb9O, mouse IgG1, and YTH862, rat IgG2b) and can induce apoptosis of phytohemagglutinin (PHA)-activated peripheral blood lymphocytes. Sensitivity to apoptosis develops after the expression of G1 markers (CD69 expression) but it is accelerated by addition of recombinant interleukin-2 (rIL-2). Blocking the IL-2 pathway by cyclosporin A, FK506, rapamycin, anti-IL-2 or CD25 antibodies, prevented the development of sensitivity to apoptosis. Addition of IL-2 and, to a lesser extent, IL-4, reversed the inhibitory effect of cyclosporin A. Conversely, rIL-7 and recombinant interferon-gamma restored proliferation of peripheral blood lymphocytes stimulated by PHA in the presence of cyclosporin A but did not restore sensitivity to class I-mediated apoptosis. Finally cells stimulated in the presence of the DNA polymerase inhibitor aphidicolin did not enter into S phase of the cell cycle but secreted IL-2 and underwent apoptosis when exposed to mAb90 or YTH862. Together, the data indicate that sensitivity of peripheral T cells to HLA class I-mediated apoptosis depends on both activation signals and IL-2 or IL-4, but does not require cell proliferation. These data suggest that YTH862 and mAb90 might be used for achieving clonal deletion of antigen-activated peripheral T cells in vivo, provided that the IL-2 pathway is not blocked by other immunosuppressive agents.
Subject(s)
Antibodies, Monoclonal/pharmacology , Apoptosis/drug effects , HLA Antigens/pharmacology , Histocompatibility Antigens Class I/pharmacology , Interleukin-2/pharmacology , Interleukin-4/pharmacology , T-Lymphocytes/drug effects , Clonal Deletion/drug effects , Drug Synergism , HLA Antigens/genetics , HLA-A Antigens/genetics , HLA-A Antigens/pharmacology , HLA-B Antigens/genetics , HLA-B Antigens/pharmacology , HLA-C Antigens/genetics , HLA-C Antigens/pharmacology , Histocompatibility Antigens Class I/genetics , Humans , Interferon-gamma/pharmacology , Interleukin-7/pharmacology , Lymphocyte Activation/immunologyABSTRACT
Our recent observation indicated that overexpression of HLA-class I antigen on pancreatic beta cells is one of the features of insulin-dependent diabetes mellitus (IDDM). To analyze the effect of class I antigen overexpression, we have introduced human HLA class I (HLA-Cw3) gene into rat pancreatic beta cell lines, RINm5F. Several stable transformants with various levels of surface expression of class I antigens have been cloned. The insulin secretion of these transfectants was analyzed to evaluate the functions of beta cells. Highly negative correlation between the level of insulin secretion and that of class I expression (correlation coefficiency: r = 0.89) has been observed. These data suggest that the overexpression of HLA class I antigen itself may impair pancreatic beta cells through a nonimmune mechanism.
