I located this abstract after finding the following post on the relative risk blog. His post is below.CD4+ T cells promote antibody production but not sustained affinity maturation during Borrelia burgdorferi infection
Rebecca A. Elsner1,2, Christine J. Hastey1,2 and Nicole Baumgarth1,2,3⇑
- Author Affiliations
Center for Comparative Medicine1
Microbiology Graduate Group2
University of California, Davis, and Dept. Pathology, Microbiology and Immunology3, School of Veterinary Medicine, University of California, Davis, Davis, California, USA
CD4 T cells are crucial for enhancing B cell-mediated immunity, supporting the induction of high-affinity, class-switched antibody responses, long-lived plasma cells and memory B cells. Previous studies showed that immune response to Borrelia burgdorferi (Bb) appear to lack robust T-dependent B cell responses, as neither long-lived plasma cells nor memory B cells form for months after infection and non-switched IgM antibodies are continuously produced during this chronic disease. This data prompted us to evaluate the induction and functionality of Bb infection-induced CD4 TFH cells. We report that CD4 T cells were effectively primed and TFH cells induced after Bb infection. These CD4 T cells contributed to the control of Bb-burden and supported the induction of Bb-specific IgG responses. However, while affinity maturation of antibodies against a prototypic T-dependent Bb protein “arthritis-related protein” (Arp) were initiated, these increases were reversed later, coinciding with the previously observed involution of germinal centers. The cessation of affinity maturation was not due to the appearance of inhibitory or exhausted CD4 T cells, or a strong induction of regulatory T cells. In vitro T-B co-cultures demonstrated that T cells isolated from Bb-infected but not Bb-immunized mice supported the rapid differentiation of B cells to antibody-secreting plasma cells rather than continued proliferation, mirroring the induction of rapid short-lived, instead of long-lived T-dependent antibody responses in vivo. The data further suggest that Bb-infection drives humoral response away from protective, high-affinity and long-lived antibody responses and towards rapid induction of strongly induced, short-lived antibodies, of limited efficacy.
The Fault in Bb Immunity
Elsner RA, Hastey CJ, Baumgarth N. CD4+ T cells promote antibody production but not sustained affinity maturation during Borrelia burgdorferi infection. Infect Immun. 2014 Oct 13.
Tick-borne infections with the Lyme disease agent, Borrelia burgdorferi (Bb), induce chronic non-resolving infections that result in tissue inflammation, most frequently “Lyme” arthritis and myocarditis and in some humans and non-human primates, but not mice, also inflammation of the central nervous system. The presence of IFN-γ producing CD4 T cells has been associated mostly with increased tissue pathology in humans and mice, and treatment of mice with anti-IL-12 mAb reduced arthritis-development in C3H mice. Thus, much focus on CD4 T cell responses to Bb has been on their pathological and pro-inflammatory role.
Early studies provided both evidence for and against a positive role of T cells on the course of B. burgdorferi-induced disease, leading some to conclude that CD4 T cells are largely dispensable for the control of Bb infection. Yet, while the anti-IL-12 treatment reduced tissue-pathology, it also increased Bb tissue-burden and the lack of IFN-γ was shown to increase joint swelling.
Others reported that the adoptive transfer of IFN-γ-secreting CD4+ T cells into Bb-infected T-cell-deficient mice promoted carditis resolution. Thus, together these data suggest that CD4 T cells can play an immune enhancing role against Bb by activating cellular immune response components, such as macrophages, and thereby reducing tissue-spirochete burden, albeit at the cost of causing tissue damage.
Another important function of CD4 T cells is their ability to enhance antibody-mediated immunity by driving affinity maturation and the development of long-lived plasma cells and memory B cells. Strong evidence links infection-induced, antibody-mediated immunity to the control of Bb tissue-burden and to disease resolution, however, not to the clearance of Bb-infection.
However, it appears unlikely that protective B cell response to Bb, a highly complex pathogen expressing many immunogenic surface antigens, is confined to T independent antibody responses alone.
Studies with multiple pathogens have demonstrated a specific role for CD4 T follicular helper cells (TFH) in the activation of B cells, including the induction of germinal centers, hallmarks of T-dependent B cell responses and birthplaces of long-term humoral immunity. Our recent studies suggested that germinal center responses were non-functional after primary Bb-infection, as long-lived antibody-secreting plasma cells and memory B cells (Elsner et al, submitted) were not induced for months after infection. Importantly, a co-administered influenza-vaccine antigen similarly failed to induce long-term immunity when given during Bb-infection (Elsner et al, submitted).
Thus, these studies pointed to specific deficits in the T-dependent B cell responses against Bb.
Here we sought to directly assess the impact of Bb-infection on the induction and functionality of CD4 T cells, particularly the induction of the TFH cells. The study confirms our previous findings on an inability of T-dependent Bb-specific germinal center-derived antibodies to be maintained long-term after Bb-infection. While CD4 T cell responses appeared effectively primed and TFH cells were induced following Bb infection, affecting a reduction of Bb-tissue burden, they differed in functionality from TFH cells induced following immunization with Bb. Infection-induced TFH cells showed a greater in vitro propensity to drive rapid B cell differentiation but not proliferation, mirroring the induction of rapid short-lived, instead of long-lived T-dependent antibody responses.
The failure to induce fully functional germinal center responses after Bb infection explain the clinical observations that humans and animals, particularly those living in endemic areas, can be frequently re-infected. They also explain the challenge in using serological evaluation of patient sera to test for prior exposure to Bb. IgG responses to Bb are known to severely decline following antibiotic treatment and this in fact is sometimes used as a sign of effective treatment. Thus, Bb serodiagnostic may greatly underestimate the number of prior exposures, not necessarily because the available tests are of low quality, but because of the pathophysiology of the Bb infection-induced B cell responses.
CD4 T cells and T-dependent antibody responses are targets for attack or evasion by many highly successful viral, bacterial, and parasitic pathogens. Thus, reducing the effectiveness of CD4 T cells during Bb-infection to support long-term humoral immunity and potentially also other mechanisms of immune protection would not be without precedent. This study may suggest that the functionality of the helper T cells induced during Bb-infection could be responsible in part for the preponderance of strong, low-affinity over long-lived high-affinity antibody responses to Bb infection. Such a shift in the quality of the humoral response would benefit the pathogen.
Ultimately, the question is whether the CD4 T cell function during Bb infection can be manipulated therapeutically to improve resistance from Bb-infection.