CR1/2 is an important suppressor of Adenovirus-induced innate immune responses and is required for induction of neutralizing antibodies.
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.
Seregin
S S
SS
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.
Aldhamen
Y A
YA
Appledorn
D M
DM
Schuldt
N J
NJ
McBride
A J
AJ
Bujold
M
M
Godbehere
S S
SS
Amalfitano
A
A
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D005822:Genetic Vectors; D007113:Immunity, Innate; D007136:Immunoglobulins / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011951:Receptors, Complement / Q000276:immunology*; D017464:Receptors, Complement 3d / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D016207:Cytokines; D007136:Immunoglobulins; D011951:Receptors, Complement; D017464:Receptors, Complement 3d