Regulation of antiviral B cell responses
Activation of antibody-producing B cells is a powerful immune defense mechanism against influenza virus infection. It also forms the basis for immune protection induced by current influenza virus vaccines. Despite their great importance, the mechanisms that regulate B cell responses are still incompletely understood. Dr. Baumgarth’s laboratory recently showed that the earliest B cell stimulation signals following influenza virus infections were provided through the type I IFN receptor, an innate immune signal. This signal was crucial for the induction of maximal B cell responses to influenza virus infection (4). These data challenge the currently held view that B cell activation is a stepwise process induced first by recognition to antigen, followed by interaction with T cells. Instead, innate immune signals can initiate and enhance B cell responses. Current efforts focus on identifying the nature and source of the IFNR signal. 12-color, 14 parameter cytometry-based assays have been developed that allow the enumeration and characterization of virus-specific B cells (5) as well as in vivo proliferating cells (6) in wildtype mice. These techniques are expected to greatly aid these studies.
The role of B-1 cells in immune defense
Various B cell subsets contribute to immune defenses to influenza virus infection by generating neutralizing antibodies. Interestingly, serum from uninfected mice and humans contains natural antibodies cross-reactive to many different strains of influenza virus, even in the complete absence of prior exposure. Dr. Baumgarth and colleagues previously showed that the presence of these antibodies is necessary for protection from acute influenza virus infection. Moreover, they demonstrated that a small subset of B cells (B1 cells) is responsible for production of most natural IgM antibodies (reviewed in 3). Recent studies in the lab of Dr. Baumgarth suggest that B-1 cells also actively participate in the respiratory tract immune responses to influenza virus infection. Current studies focus on identifying the mechanisms that regulate the activation of this B cell subset. Understanding how the production of broadly cross-reactive antibodies is regulated is important, as it might lead to novel ways in which to design vaccines that generate broadly cross-protective natural antibodies.
B cell activation during B. burgdorferi infection
Dr. Barthold’s lab has previously shown that specific antibodies to B. burgdorferi, the causative agent of Lyme Disease, when passively transferred, will provide potent immune protection from de novo infection. However, infection of humans, as well as naïve mice, causes persistent infection despite the strong induction of a specific B cell response. In collaborative studies with the Barthold lab, Dr. Baumgarth aims to characterize the developing anti-bacterial B cell response to learn what might be underlying the observed immune evasion by this spirochete. Current focus is on determining the location, kinetics, and specificity of the anti-bacterial response.
The function and regulation of antigen-presenting cells (APC) in the respiratory tract
Dr Baumgarth participated in a collaborative study with Dr Y-h Chien ( Stanford University), which demonstrated that about 0.5% of all gd T cells in mice recognize and bind to a non-classical MHC molecule (T10/22) (1). A role for these T10/22 specific gd T cells in local immunity to influenza virus is indicated, since studies in the Baumgarth lab have demonstrated the up-regulation of T10/22 in respiratory tract APC (Baumgarth et al, in preparation). Dr Baumgarth’s group is now studying the functional significance of gd T cell-T10/22 interaction during acute respiratory tract infection. They aim to also determine the role of different lung APC on local immune defense regulation.
Effects of HIV infection on mucosal immunity
HIV-infected patients present with increased infection-induced lesions in the oral cavity. While current antiviral treatments (HAART) will reduce the prevalence for some of these lesions, others appear unaffected. Thus, HAART does not fully restore immune disturbances at the local mucosal level. Dr Baumgarth’s laboratory has developed sensitive gene-expression techniques to study patient biopsy material (2). Using these techniques, they have identified local chronic activation of the type I IFN system (R. Szubin and N. Baumgarth, in preparation). Ongoing studies aim to identify the effects of this chronic activation on immunity in the mucosa of the oral cavity.
