Protein found in humans
CD244 (C luster of D ifferentiation 244) also known as 2B4 or SLAMF4 is a
protein that in humans is encoded by the CD244
gene .
[5]
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 .
[6] CD244 plays a role in the regulation of the
immune system .
[7]
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 .
[6] Only these two
receptors from the
SLAMF mediate heterophilic interactions.
[8]
[7]
Gene
The
receptor CD244 is encoded by the CD244
gene located on the long arm of human
chromosome 1 .
[8] Alternatively spliced transcript variants encoding different
isoforms have been found for this
gene .
[9] CD244 was first described in
NK cells but it is also expressed in
monocytes ,
basophils ,
eosinophils ,
mast cells ,
dendritic cells , and
T cells .
[8]
[10]
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.
[9]
[6] The extracellular region of the receptor is composed of one Ig variable-like
domain and one Ig constant 2-like
domain .
[10]
[6]
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.
[9] The inhibitory signal is mediated by binding of
phosphatases
SHP1 ,
SHP2 ,
SHIP-1 or the
kinase
CsK on the third ITSM.
[6] Activating
signaling is associated with the adaptor protein
SAP .
[9]
SAP binds to phosphorylated tyrosines in ITSMs. Then it binds to the
kinase
Fyn and that enhances downstream
signaling .
[11] Binding of EAT2 is associated with both the activating and the inhibitory signal.
[9]
CD244 is expressed in all types of
NK cells ,
[9] and it activates their
cytotoxicity and
IFNγ production.
[9]
[6] It is also expressed in a subset of effector and effector memory
CD8+ T cells
[9] where the activating
signaling via CD244 enhances their
proliferation and
cytotoxic effect .
[6]
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 .
[7] 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 .
[7]
[9]
Role of CD244 in cancer
NK cells ,
T cells ,
dendritic cells , and
myeloid-derived suppressor cells in the
tumor microenvironment express CD244.
[7] 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 .
[10]
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.
[9]
See also
References
^
a
b
c
GRCh38: Ensembl release 89: ENSG00000122223 –
Ensembl , May 2017
^
a
b
c
GRCm38: Ensembl release 89: ENSMUSG00000004709 –
Ensembl , May 2017
^
"Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^
"Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^
"Entrez Gene: CD244 CD244 molecule, natural killer cell receptor 2B4" .
^
a
b
c
d
e
f
g Pahima H, Puzzovio PG, Levi-Schaffer F (July 2019). "2B4 and CD48: A powerful couple of the immune system". Clinical Immunology . 204 : 64–68.
doi :
10.1016/j.clim.2018.10.014 .
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30366105 .
S2CID
53091716 .
^
a
b
c
d
e Sun L, Gang X, Li Z, Zhao X, Zhou T, Zhang S, Wang G (2021).
"Advances in Understanding the Roles of CD244 (SLAMF4) in Immune Regulation and Associated Diseases" . Frontiers in Immunology . 12 : 648182.
doi :
10.3389/fimmu.2021.648182 .
PMC
8024546 .
PMID
33841431 .
^
a
b
c van Driel BJ, Liao G, Engel P, Terhorst C (2016).
"Responses to Microbial Challenges by SLAMF Receptors" . Frontiers in Immunology . 7 : 4.
doi :
10.3389/fimmu.2016.00004 .
PMC
4718992 .
PMID
26834746 .
^
a
b
c
d
e
f
g
h
i
j Agresta L, Hoebe KH, Janssen EM (2018).
"The Emerging Role of CD244 Signaling in Immune Cells of the Tumor Microenvironment" . Frontiers in Immunology . 9 : 2809.
doi :
10.3389/fimmu.2018.02809 .
PMC
6279924 .
PMID
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^
a
b
c Buller CW, Mathew PA, Mathew SO (July 2020).
"Roles of NK Cell Receptors 2B4 (CD244), CS1 (CD319), and LLT1 (CLEC2D) in Cancer" . Cancers . 12 (7): 1755.
doi :
10.3390/cancers12071755 .
PMC
7409338 .
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^ Dragovich MA, Mor A (July 2018).
"The SLAM family receptors: Potential therapeutic targets for inflammatory and autoimmune diseases" . Autoimmunity Reviews . 17 (7): 674–682.
doi :
10.1016/j.autrev.2018.01.018 .
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Further reading
Vaidya SV, Mathew PA (June 2006). "Of mice and men: different functions of the murine and human 2B4 (CD244) receptor on NK cells". Immunology Letters . 105 (2): 180–184.
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10.1016/j.imlet.2006.02.006 .
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16621032 .
Siu G, Strauss EC, Lai E, Hood LE (November 1986).
"Analysis of a human V beta gene subfamily" . The Journal of Experimental Medicine . 164 (5): 1600–1614.
doi :
10.1084/jem.164.5.1600 .
PMC
2188445 .
PMID
3772297 .
Latchman Y, McKay PF, Reiser H (December 1998).
"Identification of the 2B4 molecule as a counter-receptor for CD48" . Journal of Immunology . 161 (11): 5809–5812.
doi :
10.4049/jimmunol.161.11.5809 .
PMID
9834056 .
S2CID
7819238 .
Brown MH, Boles K, van der Merwe PA, Kumar V, Mathew PA, Barclay AN (December 1998).
"2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48" . The Journal of Experimental Medicine . 188 (11): 2083–2090.
doi :
10.1084/jem.188.11.2083 .
PMC
2212392 .
PMID
9841922 .
Tangye SG, Lazetic S, Woollatt E, Sutherland GR, Lanier LL, Phillips JH (June 1999).
"Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP" . Journal of Immunology . 162 (12): 6981–6985.
doi :
10.4049/jimmunol.162.12.6981 .
PMID
10358138 .
S2CID
28826299 .
Nakajima H, Cella M, Langen H, Friedlein A, Colonna M (May 1999).
"Activating interactions in human NK cell recognition: the role of 2B4-CD48" . European Journal of Immunology . 29 (5): 1676–1683.
doi :
10.1002/(SICI)1521-4141(199905)29:05<1676::AID-IMMU1676>3.0.CO;2-Y .
PMID
10359122 .
Boles KS, Nakajima H, Colonna M, Chuang SS, Stepp SE, Bennett M, et al. (July 1999).
"Molecular characterization of a novel human natural killer cell receptor homologous to mouse 2B4" . Tissue Antigens . 54 (1): 27–34.
doi :
10.1034/j.1399-0039.1999.540103.x .
PMID
10458320 .
Kubin MZ, Parshley DL, Din W, Waugh JY, Davis-Smith T, Smith CA, et al. (November 1999).
"Molecular cloning and biological characterization of NK cell activation-inducing ligand, a counterstructure for CD48" . European Journal of Immunology . 29 (11): 3466–3477.
doi :
10.1002/(SICI)1521-4141(199911)29:11<3466::AID-IMMU3466>3.0.CO;2-9 .
PMID
10556801 .
Parolini S, Bottino C, Falco M, Augugliaro R, Giliani S, Franceschini R, et al. (August 2000).
"X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells" . The Journal of Experimental Medicine . 192 (3): 337–346.
doi :
10.1084/jem.192.3.337 .
PMC
2193227 .
PMID
10934222 .
Kumaresan PR, Mathew PA (September 2000). "Structure of the human natural killer cell receptor 2B4 gene and identification of a novel alternative transcript". Immunogenetics . 51 (11): 987–992.
doi :
10.1007/s002510000237 .
PMID
11003394 .
S2CID
450708 .
Watzl C, Stebbins CC, Long EO (October 2000).
"NK cell inhibitory receptors prevent tyrosine phosphorylation of the activation receptor 2B4 (CD244)" . Journal of Immunology . 165 (7): 3545–3548.
doi :
10.4049/jimmunol.165.7.3545 .
PMID
11034353 .
Tangye SG, Cherwinski H, Lanier LL, Phillips JH (June 2000). "2B4-mediated activation of human natural killer cells". Molecular Immunology . 37 (9): 493–501.
doi :
10.1016/S0161-5890(00)00076-6 .
PMID
11163399 .
Chuang SS, Pham HT, Kumaresan PR, Mathew PA (May 2001).
"A prominent role for activator protein-1 in the transcription of the human 2B4 (CD244) gene in NK cells" . Journal of Immunology . 166 (10): 6188–6195.
doi :
10.4049/jimmunol.166.10.6188 .
PMID
11342640 .
Morra M, Simarro-Grande M, Martin M, Chen AS, Lanyi A, Silander O, et al. (September 2001).
"Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients" . The Journal of Biological Chemistry . 276 (39): 36809–36816.
doi :
10.1074/jbc.M101305200 .
hdl :
2437/230556 .
PMID
11477068 .
S2CID
39889619 .
Morra M, Lu J, Poy F, Martin M, Sayos J, Calpe S, et al. (November 2001).
"Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells" . The EMBO Journal . 20 (21): 5840–5852.
doi :
10.1093/emboj/20.21.5840 .
PMC
125701 .
PMID
11689425 .
Speiser DE, Colonna M, Ayyoub M, Cella M, Pittet MJ, Batard P, et al. (December 2001).
"The activatory receptor 2B4 is expressed in vivo by human CD8+ effector alpha beta T cells" . Journal of Immunology . 167 (11): 6165–6170.
doi :
10.4049/jimmunol.167.11.6165 .
PMID
11714776 .
Chuang SS, Kumaresan PR, Mathew PA (December 2001).
"2B4 (CD244)-mediated activation of cytotoxicity and IFN-gamma release in human NK cells involves distinct pathways" . Journal of Immunology . 167 (11): 6210–6216.
doi :
10.4049/jimmunol.167.11.6210 .
PMID
11714782 .
Bottino C, Parolini S, Biassoni R, et al. (2001). "X-linked lymphoproliferative disease: The dark side of 2b4 function". Progress in Basic and Clinical Immunology . Advances in Experimental Medicine and Biology. Vol. 495. pp. 63–7.
doi :
10.1007/978-1-4615-0685-0_9 .
ISBN
978-1-4613-5194-8 .
PMID
11774610 .
Aoukaty A, Tan R (April 2002).
"Association of the X-linked lymphoproliferative disease gene product SAP/SH2D1A with 2B4, a natural killer cell-activating molecule, is dependent on phosphoinositide 3-kinase" . The Journal of Biological Chemistry . 277 (15): 13331–13337.
doi :
10.1074/jbc.M112029200 .
PMID
11815622 .
Sivori S, Falco M, Marcenaro E, Parolini S, Biassoni R, Bottino C, et al. (April 2002).
"Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation" . Proceedings of the National Academy of Sciences of the United States of America . 99 (7): 4526–4531.
Bibcode :
2002PNAS...99.4526S .
doi :
10.1073/pnas.072065999 .
PMC
123681 .
PMID
11917118 .
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