Until now, the expression, specificity and function of the recently identified member of the signal-regulatory protein (SIRP) family, SIRP-β2, was unknown. Reporting in Blood, Marco Colonna and colleagues now show that SIRP-β2 has an important role in T-cell adhesion to antigen-presenting cells (APCs), through binding CD47, and that this co-stimulates T-cell proliferation.

So far, three members of the SIRP family of transmembrane glycoproteins have been identified: SIRP-α, SIRP-β1 and SIRP-β2. SIRP-α is an inhibitory receptor that modulates macrophage and dendritic-cell function after it binds CD47 and undergoes phosphorylation of its cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). By contrast, SIRP-β1 lacks ITIMs but associates with the adaptor protein DAP12, through a lysine residue in its transmembrane domain, to mediate activating signals. SIRP-β2, however, lacks both ITIMs and the transmembrane lysine residue, so the authors proposed that it might be involved in cell–cell adhesion rather than in promoting inhibition or activation.

First, the authors showed that, unlike SIRP-α and SIRP-β1 (which are mainly expressed by myeloid cells), SIRP-β2 is expressed by T cells and activated natural killer cells. But similar to SIRP-α, SIRP-β2 binds CD47, although the affinity of this interaction is lower for SIRP-β2 than for SIRP-α. Expression of SIRP-β2 allowed T cells to adhere to cells expressing CD47. Moreover, the SIRP-β2–CD47 interaction between T cells and APCs promoted antigen-specific T-cell proliferation and co-stimulated T-cell activation to a similar extent to ligation of the co-stimulatory molecule CD28.

These results considerably extend our current knowledge of this new SIRP-family member, and they implicate SIRP-β2 as an important molecule in the regulation of T-cell responses.