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The maternal immune system during pregnancy
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Innate effector cells include NK cells, which are of lymphocytic lineage. In contrast to other lymphocytes, NK cells do not possess the CD3 complex or clonally expand in response to antigen stimulation. NK cells do possess many activating and inhibitory receptors of two major structural classes, those of the immunoglobulin superfamily [killer immunoglobulin-like receptors (KIRs) and LIRs] and of the C-type lectin-like family (Ly49, NKG2D, and CD94/NKG2) (39). These receptors recognize cell surface molecules, such as major histocompatibility complex (MHC)-1 glycoproteins and their structural relatives. The balance between activating and inhibiting signals determines the behavior of the NK cell. If the balance favors activation, the NK cell kills the target cell in much the same way as a cytotoxic T-lymphocyte, by forming an immunologic synapse, perforating the target cell membrane, and infusing granzyme into the cell, which initiates apoptosis of the target cell.
Intraepithelial T cells: Specialized T cells at epithelial surfaces
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Other molecules associated with immune regulation, such as LAG-3, CTLA-4, PD-1, and TGF-β, together with the SLAM-related receptor 2B4 and several members of the killer-cell immunoglobulin-like receptors, KIR or Ly49 (Ly49 A, E, and G), may further regulate the activation status of high-affinity autoreactive nIETs. The NK-inhibitory receptors suppress cytotoxicity and cytokine secretion; however, 2B4 can also function as an activation receptor and under certain conditions even promote cytotoxicity. The dual expression of activating and inhibitory receptors is consistent with their “activated yet quiescent” state, which indicates that nIETs may gain full activation status for self-based protective and/or regulatory functions in response to self-antigen-based induction signals. In support of this, in a model of induced colitis, TCRαβ+ DN nIETs were able to prevent inflammation mediated by non-self specific naive CD4+CD45RBhi donor T cells. In addition, their agonist self-antigen-based thymic functional differentiation, their cytolytic phenotype, and their early seeding and strategic location in the gut epithelium all suggest that they might serve an important role in maintaining and protecting the mucosal barrier at the time of gut colonization and before an exogenous-antigen-induced defence layer of iIETs has been formed (see Figure 6.3).
Fc Receptors
Published in Maurizio Zanetti, J. Donald Capra, The Antibodies, 1999
Killer Cell Inhibitory Receptors (KIRs) are receptors for MHC class I molecules [282]. They are expressed by NK cells [283–285] and by a subset of T lymphocytes [286]. When they recognize MHC class I molecules on the surface of target cells, KIRs inhibit cell-mediated cytotoxicity of the three types — NK cytotoxicity, ADCC and CTL-mediated cytotoxicity — triggered by NK cell receptors, FcγRIIIA and TCR respectively [287]. The intracytoplasmic domain of KIRs contains two YxxL/V motifs. When expressed in RBL cells and coaggregated with FcɛRI or with chimeric molecules having the intracytoplasmic domain of TCRζ, KIRs inhibited serotonin release as FcγRIIB did [288]. Like FcR, KIRs belong to two distinct superfamilies of molecules. Human KIRs that are members of the IgSF, and murine KIRs (Ly49) that are C-type lectins [289] were described first. The intracytoplasmic domain of murine KIRs contains one YxxL motif. Recently, lectin-like KIRs were described on human NK cells. They are heterodimers made of CD94, a transmembrane molecule whose extracellular domains bind to MHC class I molecules but which has no IC domain, associated with a molecule of the NKG2 family which may function as a signal transduction subunit [290]. NKG2A and NKG2B have two YxxL motifs in their intracytoplasmic domain.
Enhanced protection of C57 BL/6 vs Balb/c mice to melanoma liver metastasis is mediated by NK cells
Published in OncoImmunology, 2018
Friedrich Foerster, Sebastian Boegel, Rosario Heck, Geetha Pickert, Nina Rüssel, Sebastian Rosigkeit, Matthias Bros, Stephanie Strobl, Leonard Kaps, Misbah Aslam, Mustafa Diken, John Castle, Ugur Sahin, Andrea Tuettenberg, Ernesto Bockamp, Detlef Schuppan
Moreover, the two mouse strains are routinely used as background for genetically modified organisms. Apart from their Th1-/Th2-polarization, C57 BL/6 and Balb/c mice are also known to differ with regard to their NK cell capabilities: C57 BL/6 NK cells produce higher cytotoxicity against xenogeneic Chinese hamster ovary (CHO) cells than Balb/c mice.36 Moreover, Balb/c mice are susceptible to murine CMV infection, which is favored by low NK cell activity, while C57 BL/6 mice are resistant, and in vivo depletion of NK cells in C57 BL/6 mice renders them susceptible to CMV infection.37 Specifically, Balb/c and C57 BL/6 mice differ regarding their Ly49 genes – the murine homologues of the NK cell Ig-related receptor (KIR) in humans – with Balb/c mice lacking the Ly49 d and Ly49 h gene.38 In this vein, the immunosurveillance towards MHC I-deficient cancers has been shown to be Ly49-dependent,39 with the superior capacity of C57 BL/6 mice to kill CHO cells being attributable to the Ly49 d receptor,40 and the resistance of C57 BL/6 mice against murine CMV infection to the Ly49 h gene.41-45 In addition, there are several environmental modulators of NK cell activity. Interestingly, CMV infection leads to a cytokine storm in Balb/c mice as part of which interferon-γ is highly elevated without playing a pathogenic role.46 For example, exercise47 and IL-21,48 which is secreted by natural killer T cells, T follicular helper cells and TH17 cells and signals via the JAK–STAT, the MAPK as well as the PI3 K-AKT pathways,49 stimulate the anti-metastatic activity of NK cells against B16F10 metastasis in C57 BL/6 mice.
The inhibitory NKR-P1B receptor regulates NK cell-mediated mammary tumor immunosurveillance in mice
Published in OncoImmunology, 2023
Raghd Al Olabi, Abd El Aziz Hendy, Mohamad Basem Alkassab, Karla Alnajm, Manahel Elias, Mary Ibrahim, James R. Carlyle, Andrew P. Makrigiannis, Mir Munir A Rahim
Increased susceptibility to mammary tumors in NKR-P1B-deficient mice is not completely unexpected since mammary tumors in MMTV-PyVT are composed of a large proportion of cells devoid of Clr-b expression, and NKR-P1B-deficient NK cells display impaired ‘missing-self’ response against Clr-b-deficient target cells.29 NKR-P1B+ NK cells could mediate a Clr-b-dependent ‘missing-self’ response against MMTV-PyVT mammary tumors, hence delaying the development of mammary tumors in WT mice. This is similar to the increased susceptibility of NKCKD mice, which lack expression of inhibitory Ly49C/I receptors for self-class I major histocompatibility (MHC-I) molecules, to develop mammary tumors induced by the injection of MHC-I-deficient but not MHC-I-sufficient E0771 mammary adenocarcinoma cells into the mammary glands.9 The ‘missing-self’ response against MHC-I-deficient target cells is impaired in NKCKD mice, and hence, they display an increased susceptibility to MHC-I-deficient tumor development.58 Similar to Ly49 receptors, the function of the NKR-P1B receptor in tumor immunosurveillance also depends on the expression of its ligand in the tumor cells. While NKR-P1B-deficient mice are more susceptible to Clr-b-deficient mammary tumors compared to WT mice, they are more resistant to B cell lymphoma, which expresses Clr-b at high levels.29 In the B cell lymphoma model, the tumor cells appear to exploit the inhibitory NKR-P1B:Clr-b interactions to inhibit NK cells in WT but not in NKR-P1B-deficient mice. It remains to be seen if Clr-b expression in mammary tumors (or other solid tumors) can also aid in evasion of NK cells by engaging the inhibitory NKR-P1B receptor.
ERAP1: a potential therapeutic target for a myriad of diseases
Published in Expert Opinion on Therapeutic Targets, 2020
Emma Reeves, Yasmin Islam, Edward James
Further reinforcement for ERAP1 as a potential target for innate and adaptive anti-tumor immunity was demonstrated in two distinct tumor models revealing tumor growth was halted in response to modulation of ERAP1. Silencing of ERAP1 in the murine T cell lymphoma, RMA, resulted in NK mediated rejection of the lymphoma in syngeneic mice. This was due to the failure of pMHC I to engage with the Ly49 C/I NK inhibitory receptors as a result of sub-optimal peptide cargo in the absence of ERAP1 [31]. In addition, we showed that a tumor specific CD8 + T cell response was elicited in ERAAP silenced CT26, resulting in tumor rejection and prolonged survival [29].