Roles of CD48 in regulating immunity and tolerance

Abstract

CD48, a member of the signaling lymphocyte activation molecule family, participates in adhesion and activation of immune cells. Although constitutively expressed on most hematopoietic cells, CD48 is upregulated on subsets of activated cells. CD48 can have activating roles on T cells, antigen presenting cells and granulocytes, by binding to CD2 or bacterial FimH, and through cell intrinsic effects. Interactions between CD48 and its high affinity ligand CD244 are more complex, with both stimulatory and inhibitory outcomes. CD244:CD48 interactions regulate target cell lysis by NK cells and CTLs, which are important for viral clearance and regulation of effector/memory T cell generation and survival. Here we review roles of CD48 in infection, tolerance, autoimmunity, and allergy, as well as the tools used to investigate this receptor. We discuss stimulatory and regulatory roles for CD48, its potential as a therapeutic target in human disease, and current challenges to investigation of this immunoregulatory receptor.

Keywords: CD244; CD48; SLAM family.

Figure 1. The SLAM locus

CD48 is located on chromosome 1 in mice, and chromosome 1q23 in humans. In mice, the SLAM locus overlaps with the lupus-susceptibility region Sle1b. The larger Sle1 lupus susceptibility locus includes additional genes including Sh2d1b (EAT-2), Sh2d1c (ERT), Slamf8 and Slamf9. A. Schematic of SLAM family genes, and the SAP adaptors EAT-2/EAT-2B, on mouse chromosome 1. B. Schematic of the Sle1 locus, highlighting the locations of the SLAM family genes within this region.

Figure 2. Comparison of expression of CD48 and ligands in humans and mice

CD48 has two binding partners, CD244 and CD2. In humans, CD58 (LFA-3) is the high affinity ligand for CD2. CD48 is widely expressed on hematopoetic cells in both mice and humans, while its ligands have more restricted patterns of expression.

Figure 3. Functions of CD48

A. CD48 interactions with CD2 in cis on T cells can promote T cell activation, by facilitating recruitment of signaling components to the TCR. B. CD48 interactions with CD2 in trans contribute to immune synapse organization, adhesion and costimulation. C. CD48 interactions with CD244 can regulate activation of NK cells and CD8+ T effector cells. D. CD48 can bind to the bacterial component FimH, through mannose residues in the GPI linkage of CD48.