1. ¹Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
2. ²Department of Pediatrics, Michigan State University, East Lansing, MI, USA
3. ³Department of Pediatrics, Duke University Medical Center, Durham, NC, USA

Correspondence: Dr A Amalfitano, 4194 Biomedical and Physical Sciences Bldg, Michigan State University, East Lansing, MI 48823, USA. E-mail: amalfit1@msu.edu

Received 9 March 2009; Revised 21 April 2009; Accepted 25 April 2009; Published online 25 June 2009.

Abstract

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.