Identification of CD4+ T Cell Epitopes in C. burnetii Antigens Targeted by Antibody Responses

Abstract

Coxiella burnetii is an obligate intracellular Gram-negative bacterium that causes acute Q fever and chronic infections in humans. A killed, whole cell vaccine is efficacious, but vaccination can result in severe local or systemic adverse reactions. Although T cell responses are considered pivotal for vaccine derived protective immunity, the epitope targets of CD4+ T cell responses in C. burnetii vaccination have not been elucidated. Since mapping CD4+ epitopes in a genome with over 2,000 ORFs is resource intensive, we focused on 7 antigens that were known to be targeted by antibody responses. 117 candidate peptides were selected from these antigens based on bioinformatics predictions of binding to the murine MHC class II molecule H-2 IAb. We screened these peptides for recognition by IFN-γ producing CD4+ T cell in phase I C. burnetii whole cell vaccine (PI-WCV) vaccinated C57BL/6 mice and identified 8 distinct epitopes from four different proteins. The identified epitope targets account for 8% of the total vaccination induced IFN-γ producing CD4+ T cells. Given that less than 0.4% of the antigens contained in C. burnetii were screened, this suggests that prioritizing antigens targeted by antibody responses is an efficient strategy to identify at least a subset of CD4+ targets in large pathogens. Finally, we examined the nature of linkage between CD4+ T cell and antibody responses in PI-WCV vaccinated mice. We found a surprisingly non-uniform pattern in the help provided by epitope specific CD4+ T cells for antibody production, which can be specific for the epitope source antigen as well as non-specific. This suggests that a complete map of CD4+ response targets in PI-WCV vaccinated mice will likely include antigens against which no antibody responses are made.

Previously undescribed grass pollen antigens are the major inducers of T helper 2 cytokine-producing T cells in allergic individuals

“…According to this notion, specific B cells internalize and process the antigen, leading to the presentation of antigen fragments bound by surface MHC class II molecules that can be recognized by specific T cells guaranteeing that the T cells deliver help to B cells specific for the same antigen (linked help). Although in some instances it has been shown that T cells can only or preferentially provide help to B cells specific for the same protein (17,18), in other systems this restriction was not the case (19,20). It was found that two proteins that are present on the same particle could function together and that T cells specific for one protein could provide help for B cells specific for the second protein (20).…”

Reduced immunogenicity of Plasmodium falciparum gamete surface antigen (Pfs48/45) in mice after disruption of disulphide bonds – evaluating effect of interferon‐γ‐inducible lysosomal thiol reductase

“…A recent study of CD4 + T‐cell responses to the malaria protein, MSP1‐33, found that specific T‐cell epitopes were capable of inducing higher titres and more protective antibodies to the larger precursor protein (MSP1‐42), and skewed immunity to a T helper type 2‐biased response . Other studies have provided evidence that interactions of CD4 + T helper cells and B cells are linked through cognate antigen‐specific epitopes . This study was designed to correlate antibody responses with specific CD4 + T‐cell responses.…”

Host-Brucella interactions and the Brucella genome as tools for subunit antigen discovery and immunization against brucellosis

“…Traditional approaches to subunit vaccine development, such as those based on protective efficacy of bacterial fractions with subsequent identification of specific protective antigens, and the use of serology to identify immuno-dominant antigens, has been a common practice (Rappuoli, 2000; Chen et al, 2011). These methods can be tedious and expensive and often give an unsatisfactory outcome.…”

“…The identification of immunogenic proteins based solely on humoral immunity is a method that is often suggested or experimentally explored, but this approach undermines or does not always correlate with immune responses determined to have clear relevance to protection against Brucella spp. and other intracellular pathogens, i.e., T cell immunity (Rappuoli, 2000; Liang et al, 2010; Chen et al, 2011; Zhao et al, 2011). The availability of complete genomic sequences for many brucellae and their hosts has made the study of functional genomics, proteomics, and immunomics in the context of host-brucellae interactions possible.…”