Abstract
Antibody‐mediated immunity is highly protective against disease. The majority of current vaccines confer protection through humoral immunity, but there is high variability in responsiveness across populations. Identifying immune mechanisms that mediate low antibody responsiveness may provide potential strategies to boost vaccine efficacy. Here, we report diverse antibody responsiveness to unadjuvanted as well as adjuvanted immunization in substrains of BALB/c mice, resulting in high and low antibody response phenotypes. Furthermore, these antibody phenotypes were not affected by changes in environmental factors such as the gut microbiota composition. Antigen‐specific B cells following immunization had a marked difference in capability to class switch, resulting in perturbed IgG isotype antibody production. In vitro, a B‐cell intrinsic defect in the regulation of class‐switch recombination was identified in mice with low IgG antibody production. Whole genome sequencing identified polymorphisms associated with the magnitude of antibody produced, and we propose candidate genes that may regulate isotype class‐switching capability. This study highlights that mice sourced from different vendors can have significantly altered humoral immune response profiles, and provides a resource to interrogate genetic regulators of antibody responsiveness. Together these results further our understanding of immune heterogeneity and suggest additional research on the genetic influences of adjuvanted vaccine strategies is warranted for enhancing vaccine efficacy.
Highlights
Antibody-mediated immunity provides both short-term protection from pathogens and long-lived immunological memory for the lifetime of an organism
We investigated the response to NP-OVA in incomplete Freund’s adjuvant (IFA), and BALB/c A mice produced significantly lower NP-specific and total IgG1, IgG2a and IgE antibodies following adjuvanted immunization (Figure 1b, c)
We examined the affinity of NP-specific antibodies as a readout of affinity maturation efficiency; a small but significant difference in NP-specific IgG1 affinity was observed between the substrains (Supplementary figure 2f). These results demonstrate that the reduced capability of low-responder BALB/c A germinal center (GC) B cells to undergo productive class switching (C-S) leads to reduced antigen-specific IgG plasma cells forming from the GC response, which in turn infers the altered magnitude of the immunization-induced class-switched antibody response
Summary
Antibody-mediated immunity provides both short-term protection from pathogens and long-lived immunological memory for the lifetime of an organism. Antibody production can be elicited via T-dependent and -independent responses, through cognate antigen binding to the B-cell receptor.[9,10,11,12,13,14] In a T-dependent response, activated B cells can differentiate to germinal center (GC) B cells with provision of signals from pre-T follicular helper (Tfh) cells and form a germinal center structure within the lymphoid tissue.[15,16] Alternatively, activated B cells may form an extra follicular antibody response, a fate shared with B cells eliciting response to Tindependent antigen.[17,18,19] Provision of signals, such as CD40 and cytokine, induce class-switch recombination (CSR) within activated B cells.[20,21,22] This switch mechanism alters the immunoglobulin (Ig) isotype encoded by the B cell through a unique process of intrachromosomal deletion, and is critical for the protective antibody response because of the Ig constant region dictating the effector function of secreted antibodies.[23,24] The resulting classswitched plasma cells and memory B cells are key to meeting protective thresholds of antibody titers.[25,26,27] Dysfunction in any of these stages may lead to a low response phenotype.[28,29] A significant understanding of the mechanisms that regulate antibody production has been provided by this body of research, yet antibody response heterogeneity remains an issue for vaccinology, indicating a gap in our current knowledge of these mechanisms. Characterizing mediators of antibody responsiveness and relative contribution toward response magnitude will determine factors contributing to population heterogeneity and much needed strategies to boost vaccine efficacy
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