CD48

Official Full Name

CD48 molecule

Organism

Homo sapiens

GeneID

962

Background

This gene encodes a member of the CD2 subfamily of immunoglobulin-like receptors which includes SLAM (signaling lymphocyte activation molecules) proteins. The encoded protein is found on the surface of lymphocytes and other immune cells, dendritic cells and endothelial cells, and participates in activation and differentiation pathways in these cells. The encoded protein does not have a transmembrane domain, however, but is held at the cell surface by a GPI anchor via a C-terminal domain which maybe cleaved to yield a soluble form of the receptor. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

Synonyms

BCM1; BLAST; hCD48; mCD48; BLAST1; SLAMF2; MEM-102;

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Detailed Information

The CD48 gene encodes a cell surface glycoprotein that belongs to the CD2 subset of the signaling lymphocytic activation molecule (SLAM) family. The protein is GPI-anchored, meaning it is covalently attached to the outer leaflet of the plasma membrane via a glycosylphosphatidylinositol (GPI) moiety rather than spanning the membrane through a transmembrane domain. Its extracellular region contains a single N-terminal Ig-like V-set domain, which is essential for ligand interactions. Because CD48 lacks a cytoplasmic domain, it cannot directly transduce signals and relies on cooperation with other transmembrane signaling molecules for functional activity.

CD48 exhibits a broad expression profile, present on most hematopoietic cells including T cells, B cells, NK cells, dendritic cells, and granulocytes, as well as on some non-hematopoietic cells, such as endothelial cells. The gene undergoes alternative splicing, producing multiple isoforms and adding complexity to its functional regulation. Additionally, its GPI anchor can be cleaved by specific phospholipases, generating soluble CD48 that may participate in long-range intercellular communication.

Biological Significance

CD48 functions as a key co-stimulatory and adhesion molecule, mediating interactions in trans or cis that are critical for immune synapse formation and lymphocyte activation. While it cannot signal on its own, CD48 serves as a ligand-presenting molecule for multiple receptors, most notably 2B4 (CD244). 2B4 is expressed on NK cells and cytotoxic T cells, and its engagement with CD48 triggers phosphorylation of 2B4's intracellular immunoreceptor tyrosine switch motifs, recruiting signaling adaptors such as SAP (SLAM-associated protein). In the presence of SAP, this interaction transmits activating signals, enhancing NK and T cell cytotoxicity, cytokine production, and immune synapse stability, thus boosting clearance of virus-infected or tumor cells. In SAP-deficient conditions, however, the same interaction can deliver inhibitory signals, explaining certain immunodeficiency disease mechanisms.

Figure 1. CD244 is a transmembrane receptor that binds CD48 with high affinity. (Sun L, et al., 2021)

CD48 also interacts directly with CD2 on T cells, strengthening T cell–antigen-presenting cell adhesion and facilitating recruitment of LCK and LAT to the TCR/CD3 complex, lowering activation thresholds and amplifying TCR signaling. Through these multifaceted interactions, CD48 acts as a bridge between innate and adaptive immunity, finely tuning the initiation, strength, and resolution of immune responses.

Clinical Relevance

CD48's clinical importance lies in its association with immunodeficiency, tumor immunity, and potential therapeutic targeting. A clear example is X-linked lymphoproliferative disease type 1 (XLP1), caused by mutations in the SH2D1A gene encoding SAP. Without functional SAP, interactions between 2B4 on cytotoxic lymphocytes and CD48 on target cells switch from activating to strongly inhibitory, preventing NK and CD8+ T cells from effectively eliminating EBV-infected B cells, leading to fatal infectious mononucleosis, lymphoma, or immunoglobulin deficiencies. This highlights the critical role of the CD48–2B4–SAP axis in controlling herpesvirus infections and identifies it as a diagnostic and therapeutic target in XLP1.

In tumor immunity, CD48 is highly expressed on various hematologic malignancies and some solid tumors, presenting potential avenues for immunotherapy. Tumor-associated CD48 may over-engage 2B4 on effector cells, exhausting or dysregulating NK and T cell responses, thus promoting immune evasion. Targeted therapies, including CD48-specific antibodies capable of antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP), are being explored. Its GPI-anchor makes CD48 a promising target for CAR-T or bispecific antibody design.

CD48 also serves as an entry receptor for some viruses, such as measles virus, further emphasizing its role in host-pathogen interactions. Continued research into CD48 regulation across immune cell subsets and disease contexts may inform strategies to enhance immunity against infections and tumors or inhibit pathological immune responses in autoimmune or lymphoproliferative disorders.

References

Brown MH, Boles K, van der Merwe PA, et al. 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48. J Exp Med. 1998;188(11):2083–2090.
Morra M, Howie D, Grande MS, et al. X-linked lymphoproliferative disease: a progressive immunodeficiency. Annu Rev Immunol. 2001;19:657–682.
Sun L, Gang X, Li Z, et al. Advances in Understanding the Roles of CD244 (SLAMF4) in Immune Regulation and Associated Diseases. Front Immunol. 2021 Mar 24;12:648182.

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