Infection with the Lyme disease agent Borrelia burgdorferi (Bb) induces antibody responses that resolve arthritis symptoms and decrease bacterial burden, yet are ultimately incapable of clearing infection. Reinfection after antibiotic treatment is commonly reported suggesting a potential insufficiency in adaptive immune response induction to Bb. CD4 T helper cells are critical for induction of humoral memory responses and the induction of ongoing antibody responses. Paradoxically, their depletion in mouse models of the disease were shown to only moderately change the course of Bb infection. This could indicate that CD4 T cells are redundant and thus dispensable for the induction of protective Bb-specific antibody responses. However, given the inability of even the immunocompetent host to clear Bb infection, the data may suggest that CD4 T cell responses are either not induced, or are functionally suboptimal during Bb infection preventing the induction of fully protective and long-lived antibody-mediated immunity to Bb. The objective of this dissertation was therefore to determine the quality of the T-dependent humoral immune response to Bb and to study the induction and functionality of the CD4 T helper cell response.
Studies outlined in Chapter 2 utilized a mouse model of Bb infection to measure the induction of CD4 T cell-dependent and –independent Bb-specific antibody responses. Identifying prototypic Bb -antigens that induce these responses, we found that neither long-lived plasma cells nor memory B cells were induced to either type of antigen. Strikingly, the immunocompetent host not only failed to induce long-term immunity to Bb infection, it was also unable to mount long-lived immunity to an unrelated vaccine-antigen. These findings correlated with the fate of germinal center responses after Bb infection, CD4 T cell-dependent hallmarks of long-term adaptive immunity, that were only transiently induced and that appeared structurally different from those induced following vaccination with Bb-antigen. Most notably, these germinal centers lacked complement deposition on the follicular dendritic cell network.
To understand the role of CD4 T cells in this failure of robust germinal center response induction, we used a mouse model of influenza infection, known to produce strong long-lived immunity, to establish flow cytrometric and immunohistochemical approaches to differentiate follicular- from germinal center- resident CD4 T follicular helper cells. For that we used a mouse model of influenza infection, known for its effective induction of highly protective, T-dependent B cell responses. Chapter 3 outlines these studies, which identified differential expression of the chemokine receptors CXCR4 and CXCR5 together with other activation markers as able to resolve and enumerate these crucial helper populations.
Chapter 4 used the methodologies developed in Chapter 3 to assess CD4 T cell responses in the mouse model of Bb infection. The studies showed that CD4 T cells were required for control of bacterial burden. While antibody affinity maturation to the CD4 T cell-dependent antigen Arp was initiated, it was not maintained long-term. Instead, overall avidity of Arp-specific antibodies declined after a peak around 6 weeks with kinetics that correlated with the cessation of germinal center responses. However, CD4 T cells were effectively primed, and T follicular helper cells, both those in follicles and those in germinal centers appeared to develop normally. Thus a lack of T cell activation did not explain the un-sustained antibody affinity maturation or the previously observed collapse of germinal center responses. Functionally, however these cells differed from those induced by immunization with Bb, in that they more strongly supported B cell antibody production, but not B cell proliferation, which is critical for sustained germinal center reactions. These findings mimic the induction of high titers of only short-lived antibodies in vivo after Bb infection, described in Chapter 2. Collectively, this study shows that Bb infection suppresses the induction of long-lived T-dependent humoral immunity. CD4 T helper cells are induced, but their functionality appears compromised. Future studies will reveal whether these cells are direct or indirect targets of Bb infection-induced immune suppression.
|Commitee:||Barthold, Stephen W., Solnick, Jay V.|
|School:||University of California, Davis|
|School Location:||United States -- California|
|Source:||DAI-B 76/04(E), Dissertation Abstracts International|
|Keywords:||Antibody, Borrelia burgdorferi, Cd4 t cell, Immune evasion, Immune suppression, Immunological memory|
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