CD48 is a counter-receptor for mouse CD2 and is involved in T cell activation.

Abstract

SummaryCD2 is an intercellular adhesion molecule that has been implicated in T cell activation and differentiation both in humans and mice. Although the ligand for human CD2 has been defined as LFA-3, that for murine CD2 has not been identified yet . To identify the ligand for mouse CD2, we generated a chimeric molecule consisting of the extracellular domain of mouse CD2 and human immunoglobulin (Ig)G1 Fc (mCD2Rg) . A hamster monoclonal antibody (mAb), HM48-1, was established by screening mAbs that could block the binding of mCD2Rg to T cell lines at the ligand site. The putative mouse CD2 ligand recognized by this mAb was a glycosyl phosphatidylinositol-anchored glycoprotein with an apparent molecular mass of 45 W, which were shared characteristics with human LFA-3. However, its expression was predominantly restricted to hematopoietic cells, unlike human LFA 3. Protein microsequencing analysis for the NH2-terminal 18 amino acid residues of the affinity-purified HM48-1 antigen revealed that it is almost identical with mouse CD48. This identity was further confirmed by the reactivity of HM48-1 with a soluble recombinant CD48 (sCD48) protein and the molecule recognized by a rat mAb raised against sCD48 . A rat anti-CD48 mAb blocked the mCD2Rg binding as well as HM48-1 . Moreover, sCD48 also inhibited the mCD2Rg binding to the cellular ligand . Finally, like anti-CD2 mAb, HM48-1 inhibited the phytohemagglutinin response and, when crosslinked, augmented the anti-CD3 response of splenic T cells . These results indicate that CD48 is a ligand for mouse CD2 and is involved in regulating T cell activation . C D2 has been implicated in T cell adhesion and activation (1, 2). A natural ligand for CD2 has been identified as LFA-3, which is expressed on a variety of cells, including nonhematopoietic cells in humans (3-5). CD2 and LFA-3 molecules have a structural similarity (6) and a close genetic linkage (7), suggesting that these molecules have evolved from a common precursor, which has a homotypic adhesion function-like neural cell adhesion molecule, by a gene duplication (8) . It has been proposed that the intercellular interaction between CD2 and LFA3 leads to bidirectional signaling via each molecule, resulting in activation ofboth T cells and APC (9-11) . However, it has been demonstrated that the binding of LFA-3 was not sufficient for triggering T cell activation via CD2 since the addition of anti-CD2R mAbs was required (12)(13)(14). This suggests the existence of an additional ligand corresponding to anti-CD2R mAb, but it has not been identified yet.CD48, which is known as Blast-1 in humans (15), OX-45 in rats (16), and BCM1 in mice (17), is a glycosyl phosphatidylinositol (GPI)t-anchored glycoprotein expressed on almost all T and B cells, whose function remains unknown . Molecular cloning studies revealed a high structural homology of human CD48 molecule to LFA-3 (18), suggesting that it would also function as an adhesion molecule. We describe here that CD48 is a ligand for mouse CD2 and is involved in regulating T...

NK Cells Stimulate Proliferation of T and NK Cells through 2B4/CD48 Interactions

“…The present study demonstrates that, apart from being an inhibitory or activating receptor on NK cells (38,39), 2B4 can act as a ligand for CD48 expressed on other cells. Cross-linking of CD48 by specific Ab has previously been shown to increase the proliferative response of anti-CD3-stimulated CD8 ϩ T cells (40). The present study corroborates the conclusions of that study, by demonstrating that 2B4, a natural ligand for CD48, constitutively expressed on NK cells stimulates proliferation of anti-CD3-as well as specific Ag-stimulated T cells.…”

A Critical Role for CD2 in Both Thymic Selection Events and Mature T Cell Function

“…However, in rodents, the CD2 ligand is not CD58, but rather CD48 (19). No rodent CD58 gene has been identified.…”

Ligation of the CD2 co-stimulatory receptor enhances IL-2 production from first-generation chimeric antigen receptor T cells

“…However, in contrast to aCD19z T cells, blocking antibodies to CD48 on A20hCD19 tumour cells or CD2 on T cells had no discernible effect upon IL-2 secretion In humans, the ligand for CD2 is CD58, which is structurally related to murine CD48 and is expressed on many haematopoietic cells including B cells. 11 Antibody blockade of CD58 present on Raji tumour cells resulted in a 60% reduction of IL-2 production by human T cells engrafted with the aCD19z CAR after tumour-CAR T-cell co-culture ( Figure 2d). This reduction in IL-2 production was even more pronounced when CD58 was blocked on the Nalm-6 cell line (Figure 2d) potentially due to the lack of CD80/CD86 co-stimulatory molecules expressed by this tumour line.…”

“…On the other hand, many solid tumours, such as gastric and colorectal carcinomas, have reduced/ absent CD58 expression and may benefit from the inclusion of the CD2-signalling domain in CAR design. 16 --18 However, whereas mouse aCD19z T cells can effectively eradicate long-term systemic B-cell lymphoma in syngeneic mice, 5 these aCD19z T cells fail to persist for extended periods 11 suggesting that IL-2 induced by CAR T cells through CD2 ligation is not sufficient to support aCD19z T cells. Importantly, host B cells returned to normal frequencies shortly after aCD19z T-cell depletion in this model.…”

“…Importantly, host B cells returned to normal frequencies shortly after aCD19z T-cell depletion in this model. 11 However, T cells bearing a CD28-containing CD19-specific CAR maintained a longer duration of B-cell depletion indicative of prolonged activity of the CAR T cells. 19 This observation suggests that CD28 signalling from a CAR may provide greater survival signals than that of endogenous CD2 signalling in vivo.…”