CD244

CD244 (Cluster of Differentiation 244) also known as 2B4 or SLAMF4 is a protein that in humans is encoded by the CD244 gene.

CD244 is a type-I transmembrane protein belonging to the signaling lymphocytic activation molecule family of receptors (SLAMF) which are expressed in different types of hematopoietic cells. CD244 plays a role in the regulation of the immune system.

A ligand of CD244 is CD48 (SLAMF2). CD48 also belongs to the SLAMF, it does not have an intracellular domain and it is anchored to the plasma membrane by a GPI-anchor. Only these two receptors from the SLAMF mediate heterophilic interactions.

Gene
The receptor CD244 is encoded by the CD244 gene located on the long arm of human chromosome 1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. CD244 was first described in NK cells but it is also expressed in monocytes, basophils, eosinophils, mast cells, dendritic cells, and T cells.

Structure
The receptor is composed of intracellular, transmembrane, and extracellular domains. The intracellular domain contains four intracellular tyrosine-based switch motives (ITSMs) and interacts with SH2 domain-containing proteins which are involved in the signaling and determine whether it will be activating or inhibitory. The extracellular region of the receptor is composed of one Ig variable-like domain and one Ig constant 2-like domain.

Function
CD244 can function as an activating or inhibitory receptor. The expression and availability of an adaptor protein SAP determine whether the signal is activating or inhibitory. The inhibitory signal is mediated by binding of phosphatases SHP1, SHP2, SHIP-1 or the kinase CsK on the third ITSM. Activating signaling is associated with the adaptor protein SAP. SAP binds to phosphorylated tyrosines in ITSMs. Then it binds to the kinase Fyn and that enhances downstream signaling. Binding of EAT2 is associated with both the activating and the inhibitory signal.

CD244 is expressed in all types of NK cells, and it activates their cytotoxicity and IFNγ production. It is also expressed in a subset of effector and effector memory CD8+ T cells where the activating signaling via CD244 enhances their proliferation and cytotoxic effect.

Role of CD244 in viral infections
NK cells and CD8+ T cells play a crucial role in antiviral immunity. The activating signaling via CD244 leads to the enhancement of their cytolytic activity that they use for killing infected cells. The expression of CD244 is increased but the expression of SAP is decreased during some chronic viral infections, such as HIV, HBV and HCV, and that is associated with the inhibitory signal and the exhaustion of CD8+ T cells.

Role of CD244 in cancer
NK cells, T cells, dendritic cells, and myeloid-derived suppressor cells in the tumor microenvironment express CD244. The type of the signal is determined by the ratio of expressed CD244 and adaptor protein SAP. However, inhibitory signaling has been shown to predominate in the tumor-associated immune cells.

NK cells and CD8+ T cells use their cytolytic activity to kill tumor cells. Increased CD244 expression in these cells is associated with the inhibitory signal and the exhaustion of the cells. That leads to the impaired antitumor immunity caused by decreased cytotoxicity and proliferation of NK cells and CD8+ T cells. Dendritic cells are important antigen presenting cells. CD244 expression in dendritic cells is also associated with the inhibitory signal due to the low expression of SAP and therefore, they have decreased production of proinflammatory cytokines and reduced ability to activate NK cells and T cells. Myeloid-derived suppressor cells are suppressive cells also found in tumors. Their increased number in the tumor is associated with the progression of the disease. It is known that CD244 signaling in these cells enhances their immunosuppressive capacity resulting in the reduced immune response against tumors.