Browsing by Subject "Histocompatibility Antigens Class I"

Now showing 1 - 6 of 6
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    Chlamydia trachomatis immune evasion via downregulation of MHC class I surface expression involves direct and indirect mechanisms.
    (Infectious diseases in obstetrics and gynecology, 2011-01) Ibana, Joyce A; Schust, Danny J; Sugimoto, Jun; Nagamatsu, Takeshi; Greene, Sheila J; Quayle, Alison J
    Genital C. trachomatis infections typically last for many months in women. This has been attributed to several strategies by which C. trachomatis evades immune detection, including well-described methods by which C. trachomatis decreases the cell surface expression of the antigen presenting molecules major histocompatibility complex (MHC) class I, MHC class II, and CD1d in infected genital epithelial cells. We have harnessed new methods that allow for separate evaluation of infected and uninfected cells within a mixed population of chlamydia-infected endocervical epithelial cells to demonstrate that MHC class I downregulation in the presence of C. trachomatis is mediated by direct and indirect (soluble) factors. Such indirect mechanisms may aid in priming surrounding cells for more rapid immune evasion upon pathogen entry and help promote unfettered spread of C. trachomatis genital infections.
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    KIR polymorphisms modulate peptide-dependent binding to an MHC class I ligand with a Bw6 motif.
    (PLoS pathogens, 2011-03) Colantonio, Arnaud D; Bimber, Benjamin N; Neidermyer, William J; Reeves, R Keith; Alter, Galit; Altfeld, Marcus; Johnson, R Paul; Carrington, Mary; O'Connor, David H; Evans, David T
    Molecular interactions between killer immunoglobulin-like receptors (KIRs) and their MHC class I ligands play a central role in the regulation of natural killer (NK) cell responses to viral pathogens and tumors. Here we identify Mamu-A1*00201 (Mamu-A*02), a common MHC class I molecule in the rhesus macaque with a canonical Bw6 motif, as a ligand for Mamu-KIR3DL05. Mamu-A1*00201 tetramers folded with certain SIV peptides, but not others, directly stained primary NK cells and Jurkat cells expressing multiple allotypes of Mamu-KIR3DL05. Differences in binding avidity were associated with polymorphisms in the D0 and D1 domains of Mamu-KIR3DL05, whereas differences in peptide-selectivity mapped to the D1 domain. The reciprocal exchange of the third predicted MHC class I-contact loop of the D1 domain switched the specificity of two Mamu-KIR3DL05 allotypes for different Mamu-A1*00201-peptide complexes. Consistent with the function of an inhibitory KIR, incubation of lymphocytes from Mamu-KIR3DL05(+) macaques with target cells expressing Mamu-A1*00201 suppressed the degranulation of tetramer-positive NK cells. These observations reveal a previously unappreciated role for D1 polymorphisms in determining the selectivity of KIRs for MHC class I-bound peptides, and identify the first functional KIR-MHC class I interaction in the rhesus macaque. The modulation of KIR-MHC class I interactions by viral peptides has important implications to pathogenesis, since it suggests that the immunodeficiency viruses, and potentially other types of viruses and tumors, may acquire changes in epitopes that increase the affinity of certain MHC class I ligands for inhibitory KIRs to prevent the activation of specific NK cell subsets.
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    MHC class I chain-related protein A shedding in chronic HIV-1 infection is associated with profound NK cell dysfunction.
    (Virology, 2010-10) Nolting, Anne; Dugast, Anne-Sophie; Rihn, Suzannah; Luteijn, Rutger; Carrington, Mary F; Kane, Katherine; Jost, Stephanie; Toth, Ildiko; Nagami, Ellen; Faetkenheuer, Gerd; Hartmann, Pia; Altfeld, Marcus; Alter, Galit
    Natural killer (NK) cells play a critical role in host defense against viral infections. However chronic HIV-1 infection is associated with an accumulation of dysfunctional NK cells, that poorly control viral replication. The underlying mechanisms for this NK cell mediated dysfunction are not understood. Certain tumors evade NK cell mediated detection by dampening NK cell activity through the downregulation of NKG2D, via the release of soluble NKG2D-ligands, resulting in a potent suppression of NK cell function. Here we show that chronic HIV-1 infection is associated with a specific defect in NKG2D-mediated NK cell activation, due to reduced expression and transcription of NKG2D. Reduced NKG2D expression was associated with elevated levels of the soluble form of the NKG2D-ligand, MICA, in patient sera, likely released by HIV+CD4+ T cells. Thus, like tumors, HIV-1 may indirectly suppress NK cell recognition of HIV-1-infected CD4+ T cells by enhancing NKG2D-ligand secretion into the serum resulting in a profound impairment of NK cell function.
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    NK cell education: Physiological and pathological influences.
    (Frontiers in immunology, 2023-01) Rascle, Philippe; Woolley, Griffin; Jost, Stephanie; Manickam, Cordelia; Reeves, R Keith
    Natural killer (NK) cells represent a critical defense against viral infections and cancers. NK cells require integration of activating and inhibitory NK cell receptors to detect target cells and the balance of these NK cell inputs defines the global NK cell response. The sensitivity of the response is largely defined by interactions between self-major histocompatibility complex class I (MHC-I) molecules and specific inhibitory NK cell receptors, so-called NK cell education. Thus, NK cell education is a crucial process to generate tuned effector NK cell responses in different diseases. In this review, we discuss the relationship between NK cell education and physiologic factors (type of self-MHC-I, self-MHC-I allelic variants, variant of the self-MHC-I-binding peptides, cytokine effects and inhibitory KIR expression) underlying NK cell education profiles (effector function or metabolism). Additionally, we describe the broad-spectrum of effector educated NK cell functions on different pathologies (such as HIV-1, CMV and tumors, among others).
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    The immune checkpoint molecule, VTCN1/B7-H4, guides differentiation and suppresses proinflammatory responses and MHC class I expression in an embryonic stem cell-derived model of human trophoblast.
    (Frontiers in endocrinology, 2023-01) Zhou, Jie; Tian, Yuchen; Qu, Ying; Williams, Madyson; Yuan, Ye; Karvas, Rowan M; Sheridan, Megan A; Schulz, Laura C; Ezashi, Toshihiko; Roberts, Michael R; Schust, Danny J
    The placenta acts as a protective barrier to pathogens and other harmful substances present in the maternal circulation throughout pregnancy. Disruption of placental development can lead to complications of pregnancy such as preeclampsia, intrauterine growth retardation and preterm birth. In previous work, we have shown that expression of the immune checkpoint regulator, B7-H4/VTCN1, is increased upon differentiation of human embryonic stem cells (hESC) to an in vitro model of primitive trophoblast (TB), that VTCN1/B7-H4 is expressed in first trimester but not term human placenta and that primitive trophoblast may be uniquely susceptible to certain pathogens. Here we report on the role of VTCN1 in trophoblast lineage development and anti-viral responses and the effects of changes in these processes on major histocompatibility complex (MHC) class I expression and peripheral NK cell phenotypes.
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    Xenorecognition and costimulation of porcine endothelium-derived extracellular vesicles in initiating human porcine-specific T cell immune responses.
    (American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2023-07) Li, Shu; Anwar, Imran J; Canning, Aidan J; Vo-Dinh, Tuan; Kirk, Allan D; Xu, He
    Porcine vascular endothelial cells (PECs) form a mechanistic centerpiece of xenograft rejection. Here, we determined that resting PECs release swine leukocyte antigen class I (SLA-I) but not swine leukocyte antigen class-II DR (SLA-DR) expressing extracellular vesicles (EVs) and investigated whether these EVs proficiently initiate xenoreactive T cell responses via direct xenorecognition and costimulation. Human T cells acquired SLA-I+ EVs with or without direct contact to PECs, and these EVs colocalized with T cell receptors. Although interferon gamma-activated PECs released SLA-DR+ EVs, the binding of SLA-DR+ EVs to T cells was sparse. Human T cells demonstrated low levels of proliferation without direct contact to PECs, but marked T cell proliferation was induced following exposure to EVs. EV-induced proliferation proceeded independent of monocytes/macrophages, suggesting that EVs delivered both a T cell receptor signal and costimulation. Costimulation blockade targeting B7, CD40L, or CD11a significantly reduced T cell proliferation to PEC-derived EVs. These findings indicate that endothelial-derived EVs can directly initiate T cell-mediated immune responses, and suggest that inhibiting the release of SLA-I EVs from organ xenografts has the potential to modify the xenograft rejection. We propose a secondary-direct pathway for T cell activation via xenoantigen recognition/costimulation by endothelial-derived EVs.