nk 4

Natural killer cell receptor 2B4 (2B4/CD244)is a 66 kDa type I transmembrane glycoprotein in the SLAM subgroup of the CD2 protein family. SLAM family proteins have an extracellular domain (ECD) with two or four Ig-like domains and at least two cytoplasmic immunoreceptor tyrosine-based switch motifs (ITSMs). 2B4 interacts with CD48, while other SLAM family proteins interact in a homophilic manner. The mouse 2B4 cDNA encodes a 397 amino acid (aa) precursor that includes a 19 aa signal sequence, a 207 aa ECD with one Ig-like V-type and one C2-type Ig-like domain, a 21 aa transmembrane segment, and a 150 aa cytoplasmic domain with four ITSMs. Within the ECD, mouse 2B4 shares 46% and 68% aa sequence identity with human and rat 2B4, respectively. 2B4/CD48 signaling cooperates with other receptor systems to either promote or inhibit NK and CD8+ T cell activation. The inhibitory activities are distinct from those of MHC I restricted inhibitory NK cell receptors. Ligation of 2B4 with antibodies or CD48 constructs can directly trigger inhibitory signaling or disrupt an inhibitory interaction, leading to cellular activation. 2B4 can also induce signaling through CD48.

Immunoglobulin G (IgG) is a type of antibody composed of four peptide chains—two identical heavy chains and two identical light chains arranged in a Y-shape typical of antibody monomers.There are four IgG subclasses (IgG1, 2, 3, and 4) in humans, named in order of their abundance in serum. The IgG2a isotype was able to interact very efficiently with FcgammaR, and share approximately 64-78% amino acid sequence identity with IgG1 and IgG2b in the heavy chain constant region domains, CH1, CH2 and CH3, which cause the diffrence in the interaction with complement, NK and mast cells, induction or inhibition by specific cytokines, and ability to cross the placenta.

IL-32 is a recently discovered cytokine that induces various proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6) and chemokines in both human and mouse cells through the NF-kappaB and p38 MAPK inflammatory signal pathways. It is regulated robustly by other major proinflammatory cytokines and is crucial to inflammation and immune responses. Four of the IL-32 isoforms (alpha, beta, gamma, and delta) are the most representative IL-32 transcripts, and the gamma isoform of IL-32 is the most active, although all isoforms are biologically active. IL-32, a cytokine produced mainly by T, natural killer, and epithelial cells induces significant amounts of TNFalpha and MIP-2 and increases the production of both cytokines in a dose-dependent manner. IL-32 has been implicated in inflammatory disorders, Mycobacterium tuberculosis infections, inflammatory bowel disease, and influenza A virus infection, as well as in some autoimmune diseases, such as rheumatoid arthritis, ulcerative colitis, and in the human stomach cancer, human lung cancer, and breast cancer tissues. Thus, IL-32 expression might be valuable as a biomarker for cancer.

Interleukin-18 (IL-18）is a protein which belongs to the IL-1 family. It is expressed as a 24 kDa precursor by endothelial and epithelial cells, keratinocytes, gamma δ T cells, and phagocytes. Mature mouse IL-18 shares 63% and 91% amino acid sequence identity with mouse and rat IL-18, respectively. IL-18 binds to the widely expressed IL-18 R alpha which recruits IL-18 R beta to form the signaling receptor complex. Its bioactivity is negatively regulated by interactions with IL-18 binding proteins and virally encoded IL-18BP homologs. It augments natural killer cell activity in spleen cells and stimulates interferon gamma production in T-helper type I cells. In the presence of IL-12 or IL-15, IL-18 enhances anti-viral Th1 immune responses by inducing IFN-gamma production and the cytolytic activity of CD8+ T cells and NK cells. In the absence of IL-12 or IL-15, however, IL-18 promotes production of the Th2 cytokines IL-4 and IL-13 by CD4+ T cells and basophils.

Interleukin-21 receptor (IL-21R) is a type I transmembrane glycoprotein within the class I cytokine receptor family, type 4 subfamily. IL-21R is expressed mainly on B cells, NK cells, and activated T cells, but is also found on dendritic cells, alternatively activated macrophages, intestinal lamina propria fibroblasts and epithelial cells, and keratinocytes. Both IL-21 and IL-4 are necessary for efficient B cell IgG1 production and normal germinal center architecture. B cell IL-21 R engagement induces Blimp-1(which mediates plasma cell differentiation), and is important for memory responses. IL-21R engagement on mouse NK cells enhances their cytotoxic activity and IFN-γ production. IL-21R engagement on CD8+ T cells aids control of viral infection and tumor growth; IL-21R is also necessary for sufficient numbers of regulatory T cells to combat chronic inflammation. IL-21R expression is often up-regulated in allergic skin inflammation, systemic lupus erythematosus and diffuse large B cell lymphoma (DLBCL).

Interleukin-18 is a secreted protein and it belongs to the IL-1 family. IL-18 is a proinflammatory cytokine and produced by macrophages and other cells. This cytokine can induce the IFN-gamma production of T cells. The combination of this cytokine and IL12 has been shown to inhibit IL-4 dependent IgE and IgG1 production, and enhance IgG2a production of B cells. IL-18 binding protein (IL18BP) can specifically interact with this cytokine, and thus negatively regulate its biological activity. After stimulation with IL-18, natural killer (NK) cells and certain T cells release another important cytokine called interferon-γ (IFN-γ) or type II interferon that plays an important role in activating the macrophages or other cells.

Associates with chromatin regions downstream of transcriptional start sites of active genes and thus regulates gene transcription. Chromatin interaction is mediated via the binding to tri-methylated histone H3 at 'Lys-4' (H3K4me3). Key regulator of hematopoiesis involved in terminal myeloid differentiation and in the regulation of hematopoietic stem cell (HSCs) self-renewal by a mechanism that involves DNA methylation. Also acts as an important cell cycle regulator, participating in cell cycle regulatory network machinery at multiple cell cycle stages including G1/S transition, S phase progression and mitotic entry. Recruited to E2F1 responsive promoters by HCFC1 where it stimulates tri-methylation of histone H3 at 'Lys-4' and transcriptional activation and thereby facilitates G1 to S phase transition. During myoblast differentiation, required to suppress inappropriate expression of S-phase-promoting genes and maintain expression of determination genes in quiescent cells.; Cellular ligand for NCR2/NKp44, may play a role as a danger signal in cytotoxicity and NK-cell-mediated innate immunity.

Leukocyte immunoglobulin-like receptor subfamily A member 3 is also known as CD85 antigen-like family member E, Immunoglobulin-like transcript 6, ILT-6, Leukocyte immunoglobulin-like receptor 4, LIR-4 and Monocyte inhibitory receptor HM43/HM31. In humans, it is encoded by the LILRA3 gene. It acts as soluble receptor for class I MHC antigens. Binds both classical and non-classical HLA class I molecules but with reduced affinities compared to LILRB1 or LILRB2.It is detected in B-cells, natural killer (NK) cells, peripheral blood monocytes and lung.

Lectin-like transcript 1 (LLT1) encoded by CLEC2D gene is a C-type lectin-like molecule interacting with human CD161 (NKR-P1A) receptor expressed by natural killer cells and subsets of T cells. CLEC2D transcripts were detected primarily in hematopoietic cell lines and were found to be co-induced by the same activation signals. Although very low amounts of putative soluble CLEC2D protein isoforms could be produced by transfectants, CLEC2D isoforms 2 and 4 were efficiently expressed. CLEC2D uses gene splicing to generate protein isoforms that are structurally distinct and that have different biological activities. Prostate cancer is the most common type of cancer diagnosed and the second leading cause of cancer-related death in American men. Natural Killer (NK) cells are the first line of defense against cancer and infections. NK cell function is regulated by a delicate balance between signals received through activating and inhibitory receptors. Previously, we identified Lectin-like transcript-1 (LLT1/OCIL/CLEC2D) as a counter-receptor for the NK cell inhibitory receptor NKRP1A (CD161). Interaction of LLT1 expressed on target cells with NKRP1A inhibits NK cell activation.