Elsevier

Molecular Immunology

Volume 42, Issue 4, February 2005, Pages 489-494
Molecular Immunology

Review
2B4 (CD244) is a non-MHC binding receptor with multiple functions on natural killer cells and CD8+ T cells

https://doi.org/10.1016/j.molimm.2004.07.032Get rights and content

Abstract

2B4 (CD244) is expressed by memory-phenotype CD8+ T cells and all natural killer (NK) cells. The ligand for 2B4, CD48, is expressed on hematopoietic cells. 2B4 is conserved in humans and mice, and a number of reports have linked 2B4 with activation of lymphocytes. We have employed 2B4-deficient mice and antibody blocking to analyze 2B4 function both in vitro and in vivo and found that 2B4 is a receptor with multiple functions. 2B4 is required for optimal activation of CD8+ T cells and NK cells – in this context 2B4 requires interaction with CD48 on neighboring lymphocytes, demonstrating that homotypic interaction within NK cell or T cell populations augments immunity. When 2B4 is engaged by CD48 on a target cell, 2B4 conversely inhibits NK effector function. As an inhibitory receptor, 2B4 is unconventional as it is not regulated by MHC class I molecules. In this review we will discuss the significance of these multiple functions and the events that may regulate differential 2B4 signaling outcome.

Section snippets

CD150 subfamily

The CD2 receptor family is within the immunoglobulin (Ig) superfamily and consists of type 1 transmembrane proteins with an N-terminal variable Ig domain followed by a constant two Ig domain (Sidorenko and Clark, 2003). Within the CD2 family falls the CD150 (signaling lymphocyte activation molecule, SLAM) subfamily. The receptors of this subset are defined by two or more cytoplasmic immunoreceptor tyrosine-based switch motifs (ITSM; TxYxxV/I) and include 2B4 (CD244), CD84, CD229, NTB-A, and

2B4 (CD244)

2B4, which bears four ITSM motifs, is expressed by all NK cells, a subset of memory-phenotype CD8+ αβ T cells, γδ T cells, basophils and monocytes (Garni-Wagner et al., 1993, Nakajima et al., 1999, Schuhmachers et al., 1995, Valiante and Trinchieri, 1993). In mice a “short” form of 2B4, containing only one ITSM also exists; it is generated by alternative splicing of 2B4 RNA (Stepp et al., 1999). Murine 2B4 was originally described as an activating receptor on NK cells since NK cells treated

2B4 inhibition of murine NK cells

Analysis of newly generated 2B4-deficient mice has provided the opportunity to study 2B4 physiology without relying on anti-2B4 antibodies that may be acting either as agonists or antagonists. 2B4-deficient mice are phenotypically normal (Vaidya et al., submitted). NK cell development in these mice appears to be normal, which is notable because 2B4 is expressed early during development, prior to acquisition of MHC binding inhibitory receptors, and has been suggested to have a role in

2B4 homotypic stimulation of lymphocytes

As many of the CD150 family members engage in homophilic interaction, there is the opportunity for cells expressing one of these receptors to engage the same receptors on neighboring lymphocytes in the absence of APC or target cells. Despite this possibility, there is little or no precedent for such homotypic modulation of lymphocytes occurring, or having functional consequences. It was therefore of interest to find that 2B4 and CD48, which can both be expressed in the same NK cell or

2B4 signaling

An important question regarding 2B4, and other CD150 family members, is the mechanism by which ITSM-containing receptors signal. Upon ligation, the ITSM motifs of 2B4 are phosphorylated by the Src family kinases Fyn and Lck (Nakajima et al., 2000, Sayos et al., 2000). Subsequently, 2B4 has been shown to interact with several SH2 domain containing proteins, SHP-1, -2, SAP, and EAT-2, and this is the point at which the activating and inhibitory pathways diverge (Parolini et al., 2000, Sayos et

Models for 2B4 signaling differences

It is perplexing to learn that murine 2B4 can participate in both costimulatory and inhibitory signaling pathways and begs the question as to how, or under what circumstances, 2B4 switches from one to another function. There are a few likely explanations. The first is that in the case of T–T, or NK–NK homotypic signaling, 2B4 is not actually signaling but is acting as a ligand for CD48. Several pieces of evidence support this, including the finding that CD48 can potentially signal as it binds

The evolution of non-MHC binding inhibitory receptors

The definition of self and non-self for NK cells is continuing to become more sophisticated. Initially, NK cells were characterized by their vigilance for missing- or non-self MHC class I ligands (Karre, 2002). Work on NKG2D has placed “altered- or stressed-self” within NK cell surveillance. Finally, the finding that 2B4 acts as an inhibitory receptor indicates that there is another tier of regulation. This regulation is non-MHC dependent and portrayed by other newly characterized NKR-P1 family

Acknowledgements

This work was supported by the NIH grant AI020451 (to V. Kumar) and the Medical Scientist Training Program GM07281 (to M.E. McNerney).

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