CD160 - CD160 molecule |Elisa - Clia - Antibody - Protein

Background

The CD160 molecule, encoded by the CD160 gene, is a glycoprotein primarily expressed on the surface of cytotoxic lymphocytes, including natural killer (NK) cells, NKT cells, a subset of CD8+ T cells, and certain peripheral blood T-cell populations. CD160 was first identified for its unique expression pattern on immune cells and its role in modulating cytotoxic activity, playing a critical role in immune response against tumors and infected cells. CD160 functions as a receptor that binds to a variety of ligands, notably major histocompatibility complex (MHC) class I molecules and herpesvirus entry mediator (HVEM), both of which have implications in immune activation and inhibition.

CD160 serves as an immune checkpoint, similar to other co-inhibitory receptors such as CTLA-4 and PD-1, and its signaling is implicated in modulating immune responses. Its functions in immune surveillance and regulation make it particularly significant in oncology, viral immunology, and autoimmune disorders. CD160 is also characterized by its restricted expression on peripheral blood monocytes and on cells in the gastrointestinal tract, indicating its broader role in tissue-specific immune responses and homeostasis.

Protein Structure

CD160 is a glycosylphosphatidylinositol (GPI)-anchored protein, structurally characterized by the following key domains:

Extracellular Immunoglobulin (Ig)-like Domain:

• CD160 contains a single Ig-like domain within its extracellular region, a hallmark of the immunoglobulin superfamily. This Ig-like domain is critical for binding to MHC class I molecules, allowing CD160 to engage in interactions essential for immune modulation.
• Structurally, the Ig-like domain is composed of two beta-sheets forming a beta-barrel, which supports the molecule's ability to interact with multiple ligands. The binding affinity of CD160 to both classical and non-classical MHC class I molecules is relatively broad, enabling it to participate in immune responses across various cellular contexts.

GPI Anchor:

• CD160 is anchored to the plasma membrane via a GPI moiety attached to its C-terminus, which confers mobility within the membrane and facilitates receptor clustering, an important feature for signal transduction.
• The GPI anchor not only enables its membrane localization but also limits CD160’s intracellular signaling capacity, meaning that CD160 relies on its interaction partners to mediate downstream effects.

Intracellular Domain (Minimal):

• CD160 does not have a conventional intracellular signaling domain due to its GPI-anchoring. Instead, signaling occurs through the recruitment of adaptor proteins that connect CD160 to intracellular signaling cascades.

Classification and Subtypes

CD160 does not have true isoforms like other immunoregulatory proteins; however, it can exist in two primary forms based on its expression and cellular context:

GPI-anchored CD160:

• This is the predominant form of CD160, found on the cell surface of NK cells, CD8+ T cells, and other cytotoxic lymphocytes. This form is associated with immune-modulating functions, such as cytotoxicity and cytokine production.

Soluble CD160:

• CD160 can be released in a soluble form through proteolytic cleavage, a variant that may circulate in the plasma. This soluble form of CD160 has been detected in certain pathological conditions and may act as a decoy receptor, modulating immune responses by binding to ligands without delivering cell-bound signaling.

Function and Biological Significance

CD160’s biological functions are primarily related to immune surveillance, regulation of cytotoxicity, and cytokine modulation:

Cytotoxic Modulation:

• CD160 plays a role in modulating NK cell and CD8+ T cell cytotoxicity. It enhances these cells' ability to respond to infected or malignant cells by promoting recognition through binding to MHC class I molecules. This activation results in increased production of interferon-gamma (IFN-γ), a cytokine critical for the cytotoxic response.
• On NK cells, CD160 can act as both an activating and inhibitory receptor, depending on the cellular context and the nature of the ligands it binds. This duality allows CD160 to adapt its function according to the immune environment.

Immune Checkpoint Regulation:

• Similar to immune checkpoints like PD-1, CD160 has an inhibitory role when bound to the herpesvirus entry mediator (HVEM), a member of the TNF receptor superfamily. This interaction suppresses excessive immune activation and helps regulate immune homeostasis.
• The inhibitory signal through CD160 and HVEM interaction contributes to maintaining immune tolerance, thereby preventing autoimmune damage. This mechanism is particularly relevant in tissues such as the intestines, where immune tolerance to gut flora is necessary.

Inflammation and Autoimmunity:

• CD160’s involvement in immune regulation extends to inflammatory and autoimmune responses. Elevated levels of soluble CD160 have been observed in autoimmune diseases, where they may alter normal immune responses and contribute to chronic inflammation.
• In certain chronic infections, CD160 expression can become dysregulated, leading to exhausted phenotypes in CD8+ T cells, diminishing their cytotoxic potential and allowing pathogens or tumor cells to evade immune surveillance.

Tumor Immunology:

• CD160 expression on T and NK cells is integral in tumor immunology due to its role in tumor cell recognition. CD160 can directly recognize certain tumors with altered MHC class I expression, and its activation can enhance tumor cell killing.
• The role of CD160 as an immune checkpoint also opens the possibility for therapeutic modulation in cancer. Blocking the inhibitory interaction between CD160 and HVEM could restore T and NK cell functionality, making CD160 a potential target in immunotherapy strategies for cancers with immune evasion mechanisms.

Clinical Issues

Cancer:

• CD160’s dual role in immune activation and inhibition makes it significant in cancer research, where it is considered both a biomarker and a therapeutic target. In solid tumors and hematologic malignancies, the expression of CD160 can vary, influencing how immune cells interact with tumor cells.
• Therapeutically, blocking CD160’s inhibitory interactions is being explored as a means to reinvigorate exhausted T cells in the tumor microenvironment, enhancing anti-tumor immunity.

Chronic Viral Infections:

• CD160’s function is compromised in chronic infections like HIV and hepatitis, where persistent antigen stimulation can lead to T cell exhaustion. This state, often marked by elevated CD160 expression, contributes to reduced efficacy in controlling chronic infections.
• Soluble CD160, sometimes elevated in these infections, may act as a decoy receptor, further contributing to immune dysregulation. Interventions aimed at modulating CD160 signaling could potentially reinvigorate the immune response in these chronic infection scenarios.

Autoimmune Disorders:

• CD160 dysregulation has been implicated in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. Elevated levels of soluble CD160 in these diseases correlate with increased inflammation, suggesting a role for CD160 in modulating immune responses in autoimmune pathologies.
• The therapeutic modulation of CD160, including the inhibition of its soluble form or blocking its interaction with HVEM, may help mitigate autoimmune responses in these diseases.

Summary

CD160 is a glycoprotein receptor expressed on NK cells, CD8+ T cells, and certain other immune cells, playing a multifaceted role in immune regulation, cytotoxicity, and immune checkpoint modulation. Structurally, it is characterized by a single Ig-like domain that allows it to bind to MHC class I molecules and HVEM. Its primary function lies in enhancing immune surveillance and cytotoxic response, while also acting as an immune checkpoint in certain contexts. CD160 is significant in tumor immunology, chronic infections, and autoimmune diseases, with its expression pattern and soluble forms contributing to disease pathology and providing potential therapeutic targets. As such, CD160 represents an important checkpoint molecule with relevance across various immunological disorders and cancer, positioning it as a potential target for immunotherapeutic approaches aimed at modulating immune activation and tolerance.