CD47 and SIRPs: new openings

Comment on Piccio et al, page 2421

In the present issue of Blood, Piccio and colleagues report that a member of the signal-regulatory protein (SIRP) family, SIRPβ2, is expressed by T cells, binds to CD47, and costimulates T-cell proliferation.

Within the SIRP family of cell-surface glycoproteins, SIRPα and SIRPβ1 have hitherto been identified and studied. SIRPα is highly expressed by myeloid cells and neurons, but expression has also been found on endothelial cells and a subpopulation of B cells. In myeloid cells, SIRPα has been reported to inhibit phagocytosis and cytokine production when ligated by its ubiquitously expressed cell-surface ligand CD47, a function mediated by the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of SIRPα.^1,2  The CD47-SIRPα interaction can also support cell-cell adhesion and cell migration. SIRPβ1, on the other hand, does not have any intracellular signaling motifs of its own, but functions by signaling through recruitment of the adaptor protein DAP12, resulting in stimulation of myeloid cellular functions.³  In contrast to SIRPα, SIRPβ1 does not seem to bind CD47.⁴ 

The present report on SIRPβ2 significantly extends the understanding of this family of receptors, showing that SIRPβ2, in contrast to SIRPα and SIRPβ1, is not expressed by myeloid cells, but rather by T cells and activated natural killer (NK) cells. Similar to SIRPα, SIRPβ2 binds CD47 on other cells, in this case antigen-presenting cells (APCs). However, the CD47 binding affinity is lower for SIRPβ2 than that for SIRPα. The cytoplasmic domain of SIRPβ2 does not have ITIM motifs or the capacity to bind DAP12. Instead, the authors suggest that the SIRPβ2-CD47 interaction may function to strengthen the T-cell–APC binding, thereby supporting T-cell activation. These data are supported by a recent report, where the SIRPβ2 protein was referred to as SIRPγ, and shown to bind CD47.⁵  That study showed that, by binding to CD47, both SIRPβ2/SIRPγ and SIRPα fusion proteins could induce CD47-dependent apoptosis in CD47-expressing cells.⁵ 

The present findings raise new, interesting questions about the ability of CD47 to regulate immune reactions by binding to SIRPα and SIRPβ2. Although the APCs in the present study were B cells, which may not express SIRPα, other important APCs such as dendritic cells and macrophages express this receptor. Bidirectional signaling following binding of CD47 on the T cell to SIRPα on the APC was reported to inhibit both T-cell and APC activation.²  However, it has also been shown that this interaction might have the opposite effect, resulting in costimulation of T-cell activation.^1,4  Since the CD47-SIRPα interaction could theoretically operate in parallel with the SIRPβ2-CD47 interaction reported by Piccio et al (see figure), further investigations are needed to understand how these interactions can regulate T cells and APCs in various settings of immune activation. ▪