Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Nov 28:9:2809.
doi: 10.3389/fimmu.2018.02809. eCollection 2018.

The Emerging Role of CD244 Signaling in Immune Cells of the Tumor Microenvironment

Laura Agresta  1 , Kasper H N Hoebe  2   3 , Edith M Janssen  2   3
Affiliations
Review

The Emerging Role of CD244 Signaling in Immune Cells of the Tumor Microenvironment

Laura Agresta et al. Front Immunol. .

Abstract

In cancer, immune exhaustion contributes to the immunosuppressive tumor microenvironment. Exhausted immune cells demonstrate poor effector function and sustained expression of certain immunomodulatory receptors, which can be therapeutically targeted. CD244 is a Signaling Lymphocyte Activation Molecule (SLAM) family immunoregulatory receptor found on many immune cell types-including NK cells, a subset of T cells, DCs, and MDSCs-that represents a potential therapeutic target. Here, we discuss the role of CD244 in tumor-mediated immune cell regulation.

Keywords: CD244; CD8 cytotoxic T lymphocytes +; MDSC; NK cells and cancer; immune exhaustion (IE); signaling lymphocyte activation molecule; tumor immune escape; tumor microenviroment.

PubMed Disclaimer

Figures

Figure 1
Figure 1
CD244 signaling model based on NK cell studies. CD244 binds CD48 with high affinity. Intracellular signaling is propagated via interactions with any of several SH2 domain- containing signaling molecules. Interactions with SAP (SH2D1A) propagate activating signals in NK cells. Interactions with SH2 phosphatases SHP1,SHP2, SHIP-1 propagate inhibitory signals in NK cells. Interactions with EAT2 (SH2D1B) have been shown to propagate both activating and inhibitors signals in separate studies.
Figure 2
Figure 2
Model showing how the relative concentrations of CD244 and SAP may contribute to the determination of activating versus inhibitory CD244 signaling. (A) Under normal physiologic conditions, NK cells and CD8+ T cells express CD244 at low concentrations. Provided a normal intracellular concentration of SAP is present,activating signals are propagated upon CD244-CD48 interaction. (B) When SAP concentrations are low,absent,or dysfunctional (unable to bind), such as in X-linked proliferative disease,CD244 propagates an inhibitory signal upon CD244-CD48 interaction. (C) In the setting of cancer or chronic viral infection,NK cells and CD8+ T cells express high concentrations of CD244,and normal concentrations of SAP become insufficient to saturate CD244 binding sites upon CD244-CD48 interaction; an inhibitory signal is propagated.
Figure 3
Figure 3
Increased CD244 expression on immune cells in the tumor microenvironment corresponds to increased immunosuppression via effector cell exhaustion (A,B) and increased production of immunosuppressors by myeloid derived suppressor cells (MDSCs) (C).
See this image and copyright information in PMC

References

    1. Garni-Wagner BA, Purohit A, Mathew PA, Bennett M, Kumar V. A novel function-associated molecule related to non-MHC-restricted cytotoxicity mediated by activated natural killer cells and T cells. J Immunol. (1993) 151:60–70. - PubMed
    1. Valiante NM, Trinchieri G. Identification of a novel signal transduction surface molecule on human cytotoxic lymphocytes. J Exp Med. (1993) 178:1397–406. - PMC - PubMed
    1. Schuhmachers G, Ariizumi K, Mathew PA, Bennett M, Kumar V, Takashima A. 2B4, a new member of the immunoglobulin gene superfamily, is expressed on murine dendritic epidermal T cells and plays a functional role in their killing of skin tumors. J Invest Dermatol. (1995) 105:592–6. 10.1111/1523-1747.ep12323533 - DOI - PubMed
    1. 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. (1999) 29:1676–83. - PubMed
    1. Straub C, Neulen ML, Viertlboeck BC, Göbel TW. Chicken SLAMF4 (CD244, 2B4), a receptor expressed on thrombocytes, monocytes, NK cells, and subsets of alphabeta-, gammadelta- T cells and B cells binds to SLAMF2. Dev Comp Immunol. (2014) 42:159–68. 10.1016/j.dci.2013.09.007 - DOI - PubMed

Publication types

MeSH terms

Substances