Human complement receptors 1 and 2 are well described as important regulators of innate and adaptive immune responses, having pivotal roles in regulating complement activation (CR1) and B-cell maturation/ survival. In contrast, the role of the murine homologs of CR1 and CR2 (mCR1/2) have been primarily defined as modulating activation of the adaptive immune system, with very little evidence available about the role of mCR1/2 in regulating the innate immune responses to pathogens. In this paper, we confirm that mCR1/2 plays an important role in regulating both the innate and adaptive immune responses noted after Adenovirus (Ad)-mediated gene transfer. Our results uncovered a novel role of mCR1/2 in downregulating several complement-dependent innate immune responses. We also unveiled the mechanism underlying the complement-dependent induction of neutralizing antibodies to Ad capsids as a CR1/2-dependent phenomenon that correlates with B-cell activation. These results confirm that Ad interactions with the complement system are pivotal in understanding how to maximize the safety or potency of Ad-mediated gene transfer for both gene therapy and vaccine applications.
Bibliographical noteFunding Information:
We thank Michigan State University Laboratory Animal support facility for their assistance in the humane care and maintenance of the animals utilized in this work and Michigan State University Investigative Histopathology Laboratory for performing H&E stains of liver tissues. SSS was supported by American Heart Association Midwest Affiliate Fellowship 0815660G. AA was supported by the National Institutes of Health grants RO1DK-069884, P01 CA078673, the MSU Foundation as well the Osteopathic Heritage Foundation.