Nectin and Nectin-like Ligand/Receptor Co-Signaling Molecules

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    Immunology Background

    Background

    About Nectin and Nectin-like Ligand/Receptor Co-Signaling Molecules

    Nectins and Nectin-like (Necl) molecules are cell adhesion molecules that play crucial roles in cell-cell interactions and signaling. They belong to the immunoglobulin superfamily and are involved in various physiological and pathological processes. The Nectin family consists of four members: Nectin-1, Nectin-2, Nectin-3, and Nectin-4. The Necl family comprises five members: Necl-1, Necl-2, Necl-3, Necl-4, and Necl-5. These molecules can interact with each other and with their respective receptors, collectively known as Nectin and Necl-like (Necl-Like) receptors, to mediate adhesion and co-signaling events.

    Nectin and Nectin-like molecules are involved in costimulatory signaling interactions with their receptors. These costimulatory interactions can amplify or modulate immune responses and help regulate immune cell activation and effector functions. Examples of costimulatory signaling receptors include CD226, CD96, and TIGIT, which bind to specific Nectin or Nectin-like ligands.

    Interactions between members of the CD226 axis. Dashed red lines indicate the potential for cis interactions/inhibition.Fig.1 Interactions between members of the CD226 axis. Dashed red lines indicate the potential for cis interactions/inhibition. (Conner M, et al., 2022)

    The Co-signaling Molecules Associated with Nectins and Nectin-Like Ligands/Receptors

    Key molecules Functions
    CD226 (DNAM-1, DNAX accessory molecule-1)
    • CD226 is an activating receptor expressed on various immune cells, including natural killer (NK) cells, T cells, and monocytes.
    • It interacts with specific ligands, such as CD155 (PVR) and CD112 (PVRL2), which are expressed on target cells.
    • CD226 engagement provides co-stimulatory signals, enhancing immune cell activation, cytotoxicity, and cytokine production.
    • The CD226-mediated signaling pathway involves phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in its cytoplasmic tail, leading to downstream effector functions.
    CD96 (TACTILE)
    • CD96 is an immune checkpoint receptor expressed on T cells, NK cells, and subsets of dendritic cells.
    • It interacts with CD155 (PVR) and possibly other ligands.
    • CD96 engagement can have both activating and inhibitory effects on immune responses, depending on the context.
    • The precise signaling mechanisms and downstream effects of CD96 are still being investigated.
    CRTAM (Class-I-restricted T cell-associated molecule)
    • CRTAM is a co-stimulatory receptor expressed on activated T cells, NK cells, and subsets of innate lymphoid cells.
    • It interacts with Nectin-like ligands, such as Nectin-2 (CD112) and Nectin-3 (CD113).
    • CRTAM engagement enhances immune cell activation, cytotoxicity, and cytokine production.
    • The signaling pathways downstream of CRTAM are currently under investigation.
    Pvrl2 (Nectin-2, CD112)
    • Pvrl2 is a Nectin-like ligand that interacts with various receptors, including CD226, CD96, and CRTAM.
    • Binding of Pvrl2 to these receptors can provide co-stimulatory signals, enhancing immune cell functions.
    • Pvrl2 is expressed on various cell types, including immune cells and epithelial cells, and its interactions with receptors modulate immune responses.
    PVRL3 (Nectin-3, CD113)
    • PVRL3 is another Nectin-like ligand that interacts with CRTAM.
    • The PVRL3-CRTAM interaction promotes immune cell activation and effector functions.
    • PVRL3 is expressed on certain immune cell subsets and plays a role in regulating immune responses.
    PVR (CD155)
    • PVR is a ligand for CD226, TIGIT, and PVRIG.
    • CD226 binding to PVR provides co-stimulatory signals, while TIGIT and PVRIG engagement deliver inhibitory signals, dampening immune activation.
    • PVR is expressed on various cell types, including immune cells and non-immune cells, and its interactions with receptors regulate immune responses.
    PVRIG (Poliovirus receptor-related immunoglobulin domain-containing protein)
    • PVRIG is an inhibitory receptor that competes with TIGIT for binding to PVR (CD155).
    • PVRIG engagement can dampen immune responses by inhibiting T cell activation and cytokine production.
    • The downstream signaling pathways and specific effects of PVRIG are still being studied.
    TIGIT (T cell immunoreceptor with Ig and ITIM domains)
    • TIGIT is an inhibitory receptor that competes with CD226 for binding to PVR (CD155) and potentially other ligands.
    • TIGIT engagement delivers inhibitory signals, dampening immune activation and cytotoxicity.
    • TIGIT is expressed on T cells, NK cells, and regulatory T cells, and its interactions with ligands regulate immune responses.

    Co-signaling Pathways Involving Nectin and Nectin-like Ligand/Receptor Proteins

    While Nectins and Nectin-like ligand/receptor proteins primarily function as cell adhesion molecules, their interactions with co-signaling molecules can modulate immune responses through various signaling pathways. Here are some co-signaling pathways involving Nectin and Nectin-like ligand/receptor proteins:

    Pathways Roles
    CD226 (DNAM-1) Co-signaling Pathway
    • CD226 is an activating receptor that interacts with Nectin-like ligands, including Nectin-2 (CD112) and Nectin-3 (CD113).
    • Engagement of CD226 with Nectin-like ligands provides co-stimulatory signals that enhance immune cell activation and effector functions.
    • CD226 activation leads to the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in its cytoplasmic tail.
    • This triggers downstream signaling events, such as recruitment and activation of kinases (e.g., PI3K, Fyn, ZAP-70), which mediate cellular responses, including cytokine production, cytotoxicity, and proliferation.
    TIGIT Co-signaling Pathway
    • TIGIT is an inhibitory receptor that competes with CD226 for binding to Nectin-like ligands, particularly Nectin-2 (CD112).
    • TIGIT engagement delivers inhibitory signals that dampen immune cell activation and effector functions.
    • Upon ligand binding, TIGIT recruits the phosphatases SHP-1 and SHP-2 to its cytoplasmic tail.
    • These phosphatases dephosphorylate key signaling molecules, such as kinases and adapter proteins, resulting in the downregulation of immune responses.
    PVRIG Co-signaling Pathway
    • PVRIG is an inhibitory receptor that interacts with Nectin-2 (CD112) and competes with TIGIT for binding.
    • PVRIG engagement leads to inhibitory signaling and modulation of immune responses.
    • The exact intracellular signaling pathways associated with PVRIG are not yet fully understood, and further research is needed to elucidate its downstream effects.

    Overall, the co-signaling pathways involving Nectin and Nectin-like ligand/receptor proteins can have a significant impact on immune cell activation, effector functions, and immune regulation. The activation or inhibition of these pathways through interactions with CD226, TIGIT, and potentially PVRIG can fine-tune immune responses, contributing to immune homeostasis, immune tolerance, and immune surveillance.

    Predicted structures for the CD226 axis receptors CD96, CD226, TIGIT, and PVRIG.Fig.2 Predicted structures for the CD226 axis receptors CD96, CD226, TIGIT, and PVRIG. (Conner M, et al., 2022)

    The weight of each line is representative of the relative strength of interaction. Human silhouettes signify that a motif is not present in rodents. N-gly, n-linked glycosylation; Y, tyrosine residue; ITT, immunoglobulin tail tyrosine motif; ITIM, immunoreceptor tyrosine-based inhibition motif.

    Role of Co-signaling Molecules Associated with Nectins and Ncl Ligands/Receptors in Different Diseases

    The co-signaling molecules associated with Nectins and Nectin-like ligands/receptors have been implicated in various diseases due to their roles in immune regulation and cellular interactions. Here's an overview of their involvement in different diseases:

    Cancer

    • Dysregulation of co-signaling molecules, such as CD226, CD96, TIGIT, and PVR, has been observed in cancer.
    • CD226 and CD96 interactions with their ligands can modulate anti-tumor immune responses, and their manipulation is being explored in cancer immunotherapy.
    • TIGIT, an inhibitory receptor, is often upregulated in tumors, leading to immune suppression. Targeting TIGIT signaling is being investigated as a strategy to enhance anti-tumor immune responses.
    • PVR is frequently expressed on tumor cells, and its interactions with co-signaling receptors can influence tumor immune evasion mechanisms.
    • Therapies targeting these co-signaling molecules are being developed, including antibodies and chimeric antigen receptor (CAR) T cell therapies.

    Autoimmune Diseases

    • Altered expression or function of co-signaling molecules, such as CD226, TIGIT, and CRTAM, have been implicated in autoimmune diseases.
    • In autoimmune disorders, aberrant immune activation contributes to the destruction of self-tissues.
    • Modulating the signaling pathways associated with these co-signaling molecules is being explored as a potential therapeutic approach to restore immune balance and control autoimmune responses.

    Infectious Diseases

    • Co-signaling molecules, such as CD226 and TIGIT, play roles in immune responses against infectious agents.
    • CD226 engagement can enhance immune cell functions, including cytokine production and cytotoxicity, aiding in the clearance of pathogens.
    • TIGIT, on the other hand, can dampen immune responses, potentially limiting immunopathology during infections.
    • The interplay between these co-signaling molecules and infectious agents influences the outcome of immune responses and can impact the course of infectious diseases.

    Chronic Inflammation

    • In chronic inflammatory conditions, dysregulated immune responses can lead to persistent inflammation and tissue damage.
    • Co-signaling molecules, including CD226, TIGIT, and PVR, are involved in modulating immune activation and tolerance.
    • Imbalances in their expression or interactions may contribute to the perpetuation of chronic inflammation.
    • Targeting these co-signaling pathways holds promise for therapeutic interventions aimed at controlling chronic inflammatory disorders.

    It's important to note that the roles of these co-signaling molecules in diseases are still an active area of research, and their precise contributions can vary depending on the specific disease context. Further studies are needed to fully understand their mechanisms and potential as therapeutic targets in various disease settings.

    Overview of DNAM-1-, CRTAM-, Tactile- and TIGIT-triggered immune effector functions.Fig.3 Overview of DNAM-1-, CRTAM-, Tactile- and TIGIT-triggered immune effector functions. (Hermans D, et al., 2023)

    Case Study

    Case 1: Peng YP, Xi CH, Zhu Y, et al. Altered expression of CD226 and CD96 on natural killer cells in patients with pancreatic cancer. Oncotarget. 2016;7(41):66586-66594.

    The authors evaluated the expression of CD155 in 88 pancreatic cancer tissues and 33 adjacent tissues using IHC. The results showed that the average percentage of CD155-positive cells in PC tissues and adjacent tissues was 92.64% (range, 40%-95%) and 39.52% (range, 0%-90%) respectively; the staining intensity score for CD155 was close to 3 in PC tissues and 1-3 in the adjacent tissues (A-F). The IHC scores for CD155 in PC tissues were remarkably higher than those in adjacent tissues (G). Furthermore, the level of CD155 expression did not differ significantly according to patient clinicopathological features or tumor characteristics/tumor progression, and CD155 was overexpressed in almost all the PC examples. These data indicate that CD226- and/or CD96-expressing NK cells have potential for the immune treatment of PC.

    CD155 (PVR) expression in pancreatic cancer and adjacent tissues.Fig.1 CD155 (PVR) expression in pancreatic cancer and adjacent tissues.

    Case 2: Bachelet I, Munitz A, Mankutad D, Levi-Schaffer F. Mast cell costimulation by CD226/CD112 (DNAM-1/Nectin-2): a novel interface in the allergic process. J Biol Chem. 2006;281(37):27190-27196.

    The authors aimed at determining the susceptibility of CD226 costimulatory signaling to inhibition by immune inhibitory receptors. To test this, we have treated cells with a bispecific antibody linking CD300a to IgE, which was shown to inhibit mast cell degranulation at varying concentrations prior to FcϵRI-activation. The augmented activation resulting from CD226 engagement was significantly reduced at 1 μg/ml bispecific antibody and was completely blocked at 10 μg/ml (A). The FcϵRI/CD226-induced cytosolic calcium influx followed this exact inhibitory pattern at 1 μg/ml and 10 μg/ml (B).

    CD226-induced costimulation is blocked by linking IgE and CD300a.Fig.2 CD226-induced costimulation is blocked by linking IgE and CD300a.

    References

    • Hermans D, van Beers L, Broux B. Nectin Family Ligands Trigger Immune Effector Functions in Health and Autoimmunity. Biology. 2023; 12(3):452.
    • Conner M, Hance KW, Yadavilli S, Smothers J, Waight JD. Emergence of the CD226 Axis in Cancer Immunotherapy. Front Immunol. 2022;13:914406.
    • Bachelet I, Munitz A, Mankutad D, Levi-Schaffer F. Mast Cell Costimulation by CD226/CD112 (DNAM-1/Nectin-2): A Novel Interface in the Allergic Process. J Biol Chem. 2006;281(37):27190-27196.