Herpesvirus entry mediator (HVEM) is a type I membrane protein in the TNF receptor superfamily, and it can both promote and inhibit T cell activity. HVEM is highly expressed on naïve CD4+ T cells, CD8+ T memory cells, regulatory T cells, dendritic cells, monocytes, and neutrophils. It functions as a receptor for BTLA, CD160, LIGHT/TNFSF14, and Lymphotoxin-alpha. Ligation of HVEM by LIGHT triggers T cell, monocyte, and neutrophil activation and contributes to Th1 inflammation and cardiac allograft rejection. In contrast, HVEM binding to CD160 or BTLA suppresses T cell and dendritic cell activation and dampens intestinal inflammation. HVEM enhances the development of CD8+ T cell memory and Treg function. It is additionally expressed on intestinal epithelial cells, where its binding by intraepithelial lymphocyte (IEL) expressed CD160 promotes epitheilal integrity and host defense. The herpesvirus envelope glycoprotein gD, which binds HVEM to initiate membrane fusion, can antagonize both BTLA and LIGHT binding.
Inducible T-cell costimulator, also known as activation-inducible lymphocyte immunomediatory molecule, CD278, AILIM, CVID1 and ICOS, belongs to the CD28 and CTLA4 cell surface receptor family.. ICOS contains one Ig-like V-type domain and exsits as a homodimer with disulfide-linked. ICOS is highly expressed on tonsillar T-cellsand can be induced by PMA and ionomycin, ICOS plays an important role in cell-cell signaling, immune responses, and regulation of cell proliferation. Defects in ICOS are the cause of immunodeficiency common variable type 1, which is a primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antige.
Interferon-alpha/beta receptor 1 (IFN-alpha / beta R1), also known as IFNAR1, are present in all tissues and even on the surface of most IFN-resistant cells. Isoform 1, isoform 2 and isoform 3 are expressed in the IFN-alpha sensitive myeloma cell line U266B1. Isoform 2 and isoform 3 are expressed in the IFN-alpha resistant myeloma cell line U266R. Isoform 1 is not expressed in IFN-alpha resistant myeloma cell line U266R. It interacts with STAT1 and STAT2, the interaction requires its phosphorylation at Tyr-466. It also interacts with FBXW11, the substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex.
Interleukin-33 (IL-33) belongs to the IL-1 superfamily. IL33 is highly expressed in endothelial venules found in tonsils, Peyer patches and mesenteric lymph nodes, but almost undetectable in placenta. IL33 induces the production of T helper-2 (Th2)-associated cytokines. IL-33 is a cytokine that mediates its biological effects by binding to and signals through IL1RL1/ST2 and IL-1 Receptor Accessory Protein (IL1RAP), activating intracellular molecules in the NF-κB and MAP kinase signaling pathways that drive production of type 2 cytokines from polarized Th2 cells.
Leukocyte-Associated Immunoglobulin-Like Receptor 1 (LAIR1) is a single-pass type I membrane protein. LAIR1 expressed on the majority of peripheral mononuclear cells, including natural killer (NK) cells, T-cells, B-cells, monocytes, and dendritic cells, highly in naive T-cells and B-cells. As an inhibitory receptor, LAIR1 plays a constitutive negative regulatory role on cytolytic function of natural killer (NK) cells, B-cells and T-cells. Activation by Tyr phosphorylation results in recruitment and activation of the phosphatases PTPN6 and PTPN11. It also reduces the increase of intracellular calcium evoked by B-cell receptor ligation. LAIR1 plays inhibitory role independently of SH2-containing phosphatases and modulates cytokine production in CD4+ T-cells. It down-regulates IL2 and IFNG production while inducing secretion of transforming growth factor beta, also down-regulates IgG and IgE production in B-cells as well as IL8, IL10 and TNF secretion. LAIR1 inhibits the differentiation of peripheral blood precursors towards dendritic cells. It also restrains proliferation and induces apoptosis in myeloid leukemia cell lines as well as prevents nuclear translocation of NF-kappa-B p65 subunit/RELA and phosphorylation of I-kappa-B alpha/CHUK in these cells.
SLAMF7 is a single-pass type I membrane protein and contains 1 Ig-like C2-type (immunoglobulin-like) domain. SLAMF7 is expressed in NK cells, activated B-cells, NK-cell line but not in promyelocytic, B-cell lines, or T-cell lines. Although the cytoplasmic domain of CS1 contains immunoreceptor tyrosine-based switch motifs (ITSM), which enables to recruite signaling lymphocyte activation molecule (SLAM)-associated protein (SAP/SH2D1A), it activates NK cells in the absence of a functional SAP. SLAMF7 positively regulated natural killer cell functions by a mechanism dependent on the adaptor EAT-2 but not the related adaptor SAP. However, in the absence of EAT-2, CRACC potently inhibited natural killer cell function. It was also inhibitory in T cells, which are typically devoid of EAT-2. Thus, SLAMF7 can exert activating or inhibitory influences on cells of the immune system depending on cellular context and the availability of effector proteins.
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