CD244 - CD244 molecule |Elisa - Clia - Antibody - Protein

Background

CD244, also known as 2B4, is a receptor primarily expressed on natural killer (NK) cells and subsets of T cells. CD244 is encoded by the CD244 gene and belongs to the Signaling Lymphocyte Activation Molecule (SLAM) family within the immunoglobulin superfamily. This receptor plays a key role in immune regulation, functioning as a modulator of cytotoxic responses against infected or malignant cells. CD244 interacts with its ligand, CD48, a widely expressed protein found on hematopoietic cells, allowing it to mediate immune surveillance and inflammatory responses.

CD244 has gained significant attention due to its dual role as an activating and inhibitory receptor on immune cells, where its function depends largely on the cellular context and specific signal cascades involved. Unlike many receptors that have a straightforward activating or inhibitory role, CD244 is unique in its ability to modulate immune responses through varying interactions with different proteins in NK cells and T cells.

Protein Structure

CD244 has a well-defined structure that is essential for its functional diversity, particularly in how it transmits activating or inhibitory signals. Key structural components include:

Extracellular Domain:

• The extracellular domain consists of two immunoglobulin-like (Ig-like) domains. These Ig domains are critical for binding to CD48, which is expressed on various immune cells. The two Ig domains have a conserved structure and are crucial for high-affinity ligand binding and stable interactions, enabling CD244 to perform its role in immune modulation effectively.
• Glycosylation sites within the extracellular region contribute to stability and ligand affinity, as glycosylation can influence receptor conformation and interaction with other proteins.

Transmembrane Domain:

• CD244 contains a single-pass transmembrane domain that anchors the receptor within the cell membrane. This domain provides structural integrity and stabilizes the receptor's position on the cell surface, which is essential for effective signal transduction.

Cytoplasmic Tail:

• The cytoplasmic tail of CD244 is the most complex and functionally significant part of the receptor. It contains immunoreceptor tyrosine-based switch motifs (ITSMs), which are responsible for transmitting signals into the cell. The ITSMs can recruit various signaling molecules, such as Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1), SHP-2, and SH2 domain-containing inositol-5'-phosphatase (SHIP).
• These ITSMs allow CD244 to modulate its response, either inhibiting or activating cytotoxic activity based on which signaling proteins it recruits. The recruitment of SHP-1 and SHP-2 often leads to inhibitory signaling, while the recruitment of SLAM-associated protein (SAP) can activate NK cell function.

Classification and Subtypes

CD244 is part of the SLAM family of receptors, which includes SLAM (CD150), CD229, CD84, NTB-A, Ly9, and BLAME. These receptors share structural similarities, particularly in their Ig-like extracellular domains and the presence of ITSMs in their cytoplasmic regions. However, CD244 is distinct in its dual signaling function in immune regulation.

CD244 itself does not have subtypes, as it is encoded by a single gene. However, there is evidence of isoforms due to alternative splicing, which can lead to variations in the length of the cytoplasmic tail and impact the signaling capacity. These isoforms could potentially alter CD244's regulatory roles in immune responses by influencing the availability and recruitment of specific signaling molecules.

Function and Biological Significance

CD244 functions as a modulator of immune responses through its interactions with CD48. Its primary role is to regulate the activity of NK cells and certain subsets of T cells. CD244's functions are categorized as follows:

Regulation of NK Cell Cytotoxicity:

• On NK cells, CD244 can both activate and inhibit cytotoxic activity, depending on the signaling context. When SAP is present, CD244 primarily functions as an activating receptor, promoting cytotoxic responses against target cells. SAP allows CD244 to associate with activating kinases, leading to NK cell degranulation and release of cytotoxic granules.
• Conversely, in the absence of SAP or when SHP-1 and SHP-2 are recruited, CD244 transmits an inhibitory signal, reducing NK cell cytotoxicity. This dual functionality is essential for preventing excessive immune responses and avoiding tissue damage during inflammation.

Role in T Cell Modulation:

• CD244 is also expressed on subsets of CD8+ T cells and is involved in modulating their response to chronic infections and cancer. In these cells, CD244 tends to play an inhibitory role, particularly in the context of chronic viral infections where CD244 expression is often upregulated.
• Inhibitory signaling via CD244 in CD8+ T cells has been associated with T cell exhaustion, a state in which T cells lose their effectiveness after prolonged antigen exposure. This has implications in both infectious disease and cancer immunotherapy, where CD244-mediated inhibition may contribute to immune evasion by pathogens or tumor cells.

Immune Surveillance and Inflammatory Response:

• CD244 has a broader role in immune surveillance by enabling NK cells to recognize and interact with infected or malignant cells. The interaction with CD48 on target cells allows NK cells to discriminate between healthy and abnormal cells, contributing to targeted immune responses.
• In inflammatory conditions, CD244 expression on NK cells and certain T cells can be upregulated, enhancing immune responses but also increasing the risk of tissue damage if not properly regulated.

Tolerance and Autoimmunity:

• CD244 is involved in maintaining immune tolerance by preventing overactivation of NK and T cells. Its inhibitory signaling pathways contribute to self-tolerance and prevent autoimmune reactions. However, dysregulation in CD244 signaling has been linked to autoimmune disorders, where insufficient inhibitory signaling can lead to unchecked immune responses against self-antigens.

Clinical Issues

The unique properties of CD244 in modulating immune responses make it a critical target in various clinical contexts, especially those involving immune dysregulation:

Cancer Immunotherapy:

• In cancers, CD244 is associated with the exhaustion of T cells, which can impede effective anti-tumor immunity. High CD244 expression is often observed in tumor-infiltrating lymphocytes, where it contributes to reduced T cell function and persistence in the tumor microenvironment.
• Blocking CD244 has been explored as a potential strategy to reverse T cell exhaustion, restore cytotoxic activity, and improve the effectiveness of cancer immunotherapies, especially in combination with checkpoint inhibitors like PD-1 and CTLA-4 blockers.

Chronic Viral Infections:

• In chronic infections such as HIV and hepatitis C, CD244-mediated inhibition contributes to T cell exhaustion, impairing the immune system's ability to control the infection. Therapeutic approaches targeting CD244 could potentially rejuvenate exhausted T cells, providing better viral control and improving immune responses.

Autoimmune Disorders:

• Dysregulation of CD244 signaling can contribute to autoimmune diseases, where an imbalance in activating and inhibitory signaling can lead to self-reactive immune responses. Aberrant CD244 activity has been associated with conditions like systemic lupus erythematosus (SLE), where alterations in CD244 function may contribute to increased inflammation and immune cell activation.

Bone Marrow Transplantation:

• CD244 expression on NK cells is relevant in bone marrow transplantation, where NK cell-mediated cytotoxicity against donor or recipient cells can impact graft-versus-host disease (GVHD) outcomes. Modulating CD244 activity may help regulate NK cell responses post-transplantation, potentially reducing the risk of GVHD and improving patient outcomes.

Summary

CD244 (2B4) is a versatile receptor within the SLAM family that is expressed primarily on NK cells and certain T cell subsets. Its structure, which includes an extracellular Ig-like domain for ligand binding and a cytoplasmic tail rich in ITSM motifs, allows it to serve as both an activating and inhibitory receptor. This unique feature of CD244 enables it to finely tune immune responses, either promoting or dampening cytotoxic activity based on cellular context and signal pathway interactions. CD244 plays critical roles in immune surveillance, NK cell cytotoxicity, and modulation of T cell responses during chronic infections and cancer.

Clinically, CD244 is a significant target in cancer immunotherapy and chronic viral infections, where its inhibitory signaling is associated with immune exhaustion and reduced efficacy of immune responses. It also holds potential therapeutic value in autoimmune diseases and transplant medicine due to its ability to modulate NK and T cell responses. CD244 remains an important molecule for understanding immune regulation, especially in settings where precise modulation of cytotoxicity and tolerance is required to achieve optimal clinical outcomes.