CD48 explained

CD48 antigen (cluster of differentiation 48) also known as B-lymphocyte activation marker (BLAST-1) or signaling lymphocytic activation molecule 2 (SLAMF2) is a protein that in humans is encoded by the CD48 gene.^[1]

CD48 is a member of the CD2 subfamily of the immunoglobulin superfamily (IgSF) which includes SLAM (signaling lymphocyte activation molecules) proteins, such as CD84, CD150, CD229 and CD244. CD48 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.^[1]

CD48 was the first B-cell-specific cellular differentiation antigen identified in transformed B lymphoblasts.^{[2] [3]}

Structure

The gene for CD48 is located in chromosome 1q23 and contains 4 exons, each exon encoding one of the 4 domains of CD48: signal peptide, variable (V) domain, constant 2 (C2) domain and the glycophosphatidylinositol anchor (GPI anchor). The cDNA sequence of 1137 nucleotides encodes a 243 amino acid polypeptide of about 45 kDa.^[4] It consists of a 26 amino acid signal peptide, 194 amino acids of mature CD48 (V and C2 domains) and the C-terminal 23 amino acid segment comprising the GPI anchor.^{[5] [6]} The GPI linkage of CD48 to the cell surface is through serine residue 220.^{[5] [6]} CD48 does not have a transmembrane domain, however, but is held at the cell surface by a GPI anchor via a C-terminal domain which can be cleaved to yield a soluble form of the receptor.^[1] The CD48 protein is heavily glycosylated, with five possible asparagine-linked glycosylation sites at positions 40, 44, 104, 162 and 189, respectively.^{[2] [3] [7] [8] [9]} Approximately 35-40% of the total molecular weight is attributed to the carbohydrate side chains.^{[8] [9] [10]}

Interactions

CD48 was found to have a very low affinity for CD2 with dissociation constant (

K _{D} ) < 0.5 mM.^[11] It was found that the preferred ligand of CD48 is 2B4 (CD244), which is also a member of the CD2 subfamily SLAM of IgSF expressed on natural killer cells (NK cells) and other leukocytes. The affinity of CD244 for CD48 is at K _{D} = 8 μM which is about 5 - 10 times stronger than for CD2.^{[12] [13] [14]}

Function

Cell distribution

CD48 is expressed on all peripheral blood lymphocytes (PBL) including T cells, B cells, NK cells and thymocytes.^{[3] [7] [10] [15]} It is also found on the surface of activated T cells, mast cells, monocytes and granulocytes.^[8] Like all other GPI anchor protein (GPI-AP), CD48 is deficient in erythrocytes (red blood cells).

T-cell activation

CD48 and CD2 molecular coupling together with other interaction pairs of CD28 and CD80, TCR and peptide-MHC and LFA-1 and ICAM-1 contribute to the formation of an immunological synapse between a T cell and an antigen-presenting cell.^[16] CD48 interaction with CD2 has been shown to promote lipid raft formation, T cell activation and the formation of caveolae for macrophages through cell signal transduction via GPI moieties.^{[17] [18]}

Clinical significance

CD48 is being investigated amongst other markers in research on inflammation markers and therapies for HIV/AIDS.

Heterozygous germline mutation in a patient was associated with a recurrent inflammatory syndrome resembling hemophagocytic lymphohistiocytosis.^[19]

See also

• Cluster of differentiation

References

Further reading

• Wong YW, Williams AF, Kingsmore SF, Seldin MF . Structure, expression, and genetic linkage of the mouse BCM1 (OX45 or Blast-1) antigen. Evidence for genetic duplication giving rise to the BCM1 region on mouse chromosome 1 and the CD2/LFA3 region on mouse chromosome 3 . J. Exp. Med. . 171 . 6 . 2115–30 . 1990 . 1693656 . 2187942 . 10.1084/jem.171.6.2115 .
• Fisher RC, Thorley-Lawson DA . Characterization of the Epstein-Barr virus-inducible gene encoding the human leukocyte adhesion and activation antigen BLAST-1 (CD48) . Mol. Cell. Biol. . 11 . 3 . 1614–23 . 1991 . 1847502 . 369456 . 10.1128/MCB.11.3.1614.
• Korínek V, Stefanová I, Angelisová P, Hilgert I, Horejsí V . The human leucocyte antigen CD48 (MEM-102) is closely related to the activation marker Blast-1 . Immunogenetics . 33 . 2 . 108–12 . 1991 . 1999350 . 10.1007/BF00210823 . 11414678 .
• Garnett D, Barclay AN, Carmo AM, Beyers AD . The association of the protein tyrosine kinases p56lck and p60fyn with the glycosyl phosphatidylinositol-anchored proteins Thy-1 and CD48 in rat thymocytes is dependent on the state of cellular activation . Eur. J. Immunol. . 23 . 10 . 2540–4 . 1993 . 8104794 . 10.1002/eji.1830231024 . 9747812 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Solomon KR, Rudd CE, Finberg RW . The association between glycosylphosphatidylinositol-anchored proteins and heterotrimeric G protein alpha subunits in lymphocytes . Proc. Natl. Acad. Sci. U.S.A. . 93 . 12 . 6053–8 . 1996 . 8650218 . 39187 . 10.1073/pnas.93.12.6053 . 1996PNAS...93.6053S . free .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Smith GM, Biggs J, Norris B, Anderson-Stewart P, Ward R . Detection of a soluble form of the leukocyte surface antigen CD48 in plasma and its elevation in patients with lymphoid leukemias and arthritis . J. Clin. Immunol. . 17 . 6 . 502–9 . 1998 . 9418191 . 10.1023/A:1027327912204 . 2538203 . free .
• Latchman Y, McKay PF, Reiser H . Identification of the 2B4 molecule as a counter-receptor for CD48 . J. Immunol. . 161 . 11 . 5809–12 . 1998 . 10.4049/jimmunol.161.11.5809 . 9834056 . 7819238 . free .
• Nakajima H, Cella M, Langen H, Friedlein A, Colonna M . Activating interactions in human NK cell recognition: the role of 2B4-CD48 . Eur. J. Immunol. . 29 . 5 . 1676–83 . 1999 . 10359122 . 10.1002/(SICI)1521-4141(199905)29:05<1676::AID-IMMU1676>3.0.CO;2-Y . free .
• Shin JS, Abraham SN . Glycosylphosphatidylinositol-anchored receptor-mediated bacterial endocytosis. . FEMS Microbiol. Lett. . 197 . 2 . 131–8 . 2001 . 11313125 . 10.1111/j.1574-6968.2001.tb10594.x . free .
• Tangye SG, Cherwinski H, Lanier LL, Phillips JH . 2B4-mediated activation of human natural killer cells . Mol. Immunol. . 37 . 9 . 493–501 . 2001 . 11163399 . 10.1016/S0161-5890(00)00076-6 .
• Suzuki T, Kiyokawa N, Taguchi T, Sekino T, Katagiri YU, Fujimoto J . CD24 induces apoptosis in human B cells via the glycolipid-enriched membrane domains/rafts-mediated signaling system . J. Immunol. . 166 . 9 . 5567–77 . 2001 . 11313396 . 10.4049/jimmunol.166.9.5567 . free .
• Hawash IY, Hu XE, Adal A, Cassady JM, Geahlen RL, Harrison ML . The oxygen-substituted palmitic acid analogue, 13-oxypalmitic acid, inhibits Lck localization to lipid rafts and T cell signaling . Biochim. Biophys. Acta . 1589 . 2 . 140–50 . 2002 . 12007789 . 10.1016/S0167-4889(02)00165-9 . free .
• Kim D, Hur DY, Kim YS, Lee K, Lee Y, Cho D, Kang JS, Kim YI, Hahm E, Yang Y, Yoon S, Kim S, Lee WB, Park HY, Kim YB, Hwang YI, Chang KY, Lee WJ . CM1 ligation initiates apoptosis in a caspase 8-dependent manner in Ramos cells and in a mitochondria-controlled manner in Raji cells . Hum. Immunol. . 63 . 7 . 576–87 . 2002 . 12072193 . 10.1016/S0198-8859(02)00405-6 .
• Zhu B, Davies EA, van der Merwe PA, Calvert T, Leckband DE . Direct measurements of heterotypic adhesion between the cell surface proteins CD2 and CD48 . Biochemistry . 41 . 40 . 12163–70 . 2002 . 12356317 . 10.1021/bi020296g .
• Wei J . Expression and characterisation of recombinant human CD48 and isolation of a human anti-CD48 monoclonal antibody by phage display . Journal of Chemical Technology and Biotechnology . 80 . 7 . 782–795 . 2005 . 10.1002/jctb.1238 .
• Wei J . Cytotoxic Activity of CD48 Monoclonal Antibodies Against Human Lymphoma Cells . The Open Biotechnology Journal . 2 . 219–223 . 2008 . 10.2174/1874070700802010219 . free.

Notes and References

1. Web site: Entrez Gene: CD48 CD48 molecule.
2. Thorley-Lawson DA, Schooley RT, Bhan AK, Nadler LM . Epstein-Barr virus superinduces a new human B cell differentiation antigen (B-LAST 1) expressed on transformed lymphoblasts . Cell . 30 . 2 . 415–25 . September 1982 . 6291768 . 10.1016/0092-8674(82)90239-2 . 45406805 .
3. Yokoyama S, Staunton D, Fisher R, Amiot M, Fortin JJ, Thorley-Lawson DA . Expression of the Blast-1 activation/adhesion molecule and its identification as CD48 . J. Immunol. . 146 . 7 . 2192–200 . April 1991 . 10.4049/jimmunol.146.7.2192 . 1848579 . 13131389 .
4. Del Porto P, Mami-Chouaib F, Bruneau JM, Jitsukawa S, Dumas J, Harnois M, Hercend T . TCT.1, a target molecule for gamma/delta T cells, is encoded by an immunoglobulin superfamily gene (Blast-1) located in the CD1 region of human chromosome 1 . J. Exp. Med. . 173 . 6 . 1339–44 . June 1991 . 1827826 . 2190850 . 10.1084/jem.173.6.1339 .
5. Killeen N, Moessner R, Arvieux J, Willis A, Williams AF . The MRC OX-45 antigen of rat leukocytes and endothelium is in a subset of the immunoglobulin superfamily with CD2, LFA-3 and carcinoembryonic antigens . EMBO J. . 7 . 10 . 3087–91 . October 1988 . 3181129 . 454697 . 10.1002/j.1460-2075.1988.tb03174.x.
6. Staunton DE, Fisher RC, LeBeau MM, Lawrence JB, Barton DE, Francke U, Dustin M, Thorley-Lawson DA . Blast-1 possesses a glycosyl-phosphatidylinositol (GPI) membrane anchor, is related to LFA-3 and OX-45, and maps to chromosome 1q21-23 . J. Exp. Med. . 169 . 3 . 1087–99 . March 1989 . 2466936 . 2189294 . 10.1084/jem.169.3.1087 .
7. Vaughan HA, Henning MM, Purcell DF, McKenzie IF, Sandrin MS . The isolation of cDNA clones for CD48 . Immunogenetics . 33 . 2 . 113–7 . 1991 . 1999351 . 10.1007/BF00210824 . 32479661 .
8. Staunton DE, Thorley-Lawson DA . Molecular cloning of the lymphocyte activation marker Blast-1 . EMBO J. . 6 . 12 . 3695–701 . December 1987 . 2828034 . 553839 . 10.1002/j.1460-2075.1987.tb02703.x.
9. Rudd PM, Wormald MR, Stanfield RL, Huang M, Mattsson N, Speir JA, DiGennaro JA, Fetrow JS, Dwek RA, Wilson IA . Roles for glycosylation of cell surface receptors involved in cellular immune recognition . J. Mol. Biol. . 293 . 2 . 351–66 . October 1999 . 10529350 . 10.1006/jmbi.1999.3104 .
10. Vaughan HA, Thompson CH, Sparrow RL, McKenzie IF . Hu Ly-M3--a human leukocyte antigen . Transplantation . 36 . 4 . 446–50 . October 1983 . 6623618 . 10.1097/00007890-198310000-00018 . 40061476 . free .
11. Sandrin MS, Mouhtouris E, Vaughan HA, Warren HS, Parish CR . CD48 is a low affinity ligand for human CD2 . J. Immunol. . 151 . 9 . 4606–13 . November 1993 . 10.4049/jimmunol.151.9.4606 . 7691954 . 37921171 . free .
12. Brown MH, Boles K, van der Merwe PA, Kumar V, Mathew PA, Barclay AN . 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48 . J. Exp. Med. . 188 . 11 . 2083–90 . December 1998 . 9841922 . 2212392 . 10.1084/jem.188.11.2083 .
13. Kubin MZ, Parshley DL, Din W, Waugh JY, Davis-Smith T, Smith CA, Macduff BM, Armitage RJ, Chin W, Cassiano L, Borges L, Petersen M, Trinchieri G, Goodwin RG . Molecular cloning and biological characterization of NK cell activation-inducing ligand, a counterstructure for CD48 . Eur. J. Immunol. . 29 . 11 . 3466–77 . November 1999 . 10556801 . 10.1002/(SICI)1521-4141(199911)29:11<3466::AID-IMMU3466>3.0.CO;2-9 . free .
14. Nakajima H, Colonna M . 2B4: an NK cell activating receptor with unique specificity and signal transduction mechanism . Hum. Immunol. . 61 . 1 . 39–43 . January 2000 . 10658976 . 10.1016/s0198-8859(99)00170-6 .
15. Henniker AJ, Bradstock KF, Grimsley P, Atkinson MK . A novel non-lineage antigen on human leucocytes: characterization with two CD-48 monoclonal antibodies . Dis. Markers . 8 . 4 . 179–90 . 1990 . 2088634 .
16. Malissen B . Dancing the immunological two-step . Science . 285 . 5425 . 207–208 . 1999 . 10428718 . 10.1126/science.285.5425.207 . 5731764 .
17. Mulvey MA, Hultgren SJ . Cell biology. Bacterial spelunkers . Science . 289 . 5480 . 732–733 . 2000 . 10950716 . 10.1126/science.289.5480.732 . 43466889 .
18. Loertscher R, Lavery P . The role of glycosyl phosphatidyl inositol (GPI)-anchored cell surface proteins in T-cell activation . Transplant Immunology . 9 . 2–4 . 93–96 . 2002 . 12180852 . 10.1016/s0966-3274(02)00013-8.
19. Volkmer B, Planas R, Gossweiler E, Opitz L, Mauracher A, Nüesch U, Gayden T, Kaiser D, Drexel B, Dumrese C, Jabado N, Vavassori S, Pachlopnik Schmid J: Recurrent inflammatory disease caused by a heterozygous mutation in CD48. J Allergy Clin Immunol. 2019;144(5):1441-1445.e17. doi:10.1016/j.jaci.