Mismatch between CD47 and SIRPα was found to explain age-old immunogenicity mystery

Sheep erythrocytes (SRBCs) have been used in immunological research for a very long time. It was well documented that SRBCs were highly immunogenic if injected in mice, so researchers were using it to serve as a "carrier" to enhance immune response to other, less immunogenic antigens, epitopes or haptens. Its mechanism of action was not clear.  

Now, new study in journal Immunity has showed that (a) mismatch between sheep CD47 and mouse SIRPα determined SRBCs immunogenicity in vivo, and (b) that absence of CD47 from mouse erythrocytes could convert mouse erythrocytes into "immunogenic".  

First, the authors showed that plate coated mouse SIRPα would only bind wild-type mouse erythrocytes (red blood cells). This confirmed that "do not eat me" inhibitory circuit mediated by CD47-SIRPα interaction are species-specific (though interestingly SIRPα from non-obese diabetic-prone NOD mice strain does bind strongly to human CD47).

Next the authors showed that similar to SRBCs but unlike to wild-type mouse RBCs, erythrocytes from CD47^-/- mice could activate mouse spleen dendritic cells upon adoptive transfer. (A) Interestingly, however, transfer of white blood cells from CD47^-/- mice did not activate spleen DCs; (B) Also, note that the authors failed to observe activation of spleen DCs cultured with SRBCs or CD47-deficient mouse erythrocytes in vitro.

More importantly, additional experiments showed that RBCs from CD47^-/- mice could serve as a "carrier" to enhance CD4 T cell immune response to nominal antigen, such as ovalbumin.

In summary, this study provided long overdue explanation as for immunogenicity of SRBCs. It appears that in absence of CD47-SIRPα inhibitory engagement between SRBCs and mouse spleen DCs, signals [driven by integrins and Src-family tyrosine kinases] dominates that lead to DC activation.

David Usharauli