Determining the role of Toll-like receptors in innate and adaptive immune responses to Borrelia hermsii and other antigenic targets of T cell-independent humoral immunity

Gregory S Dickinson, Thomas Jefferson University

Abstract

Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are germ line-encoded receptors expressed on a variety of immune cells that recognize evolutionarily conserved components of bacterial, viral, and protozoan organisms. These receptors have been shown to be critical for the normal functioning of both the innate and adaptive immune system. Antibody responses to a class of antigens such as polysaccharides involve B cell receptor (BCR) cross-linking, do not require T cell-help and are therefore referred to as T cell-independent (TI) antigens. Borrelia hermsii infection elicits a protective, B1b cell-mediated IgM response in a TI manner. We have found that TLR2 is the primary germ line-encoded receptor contributing to this response, suggesting that TLR2 signaling can significantly enhance BCR-mediated responses. TLR ligands can enhance primary and secondary responses to TI antigens, such as the pneumococcal polysaccharides present in commercial vaccine preparations. We found that TLR2 ligand administration enhances the persistence of antigen-specific B1b cells following immunization. Furthermore, we have found that contemporaneous TLR and BCR stimulation increases the surface expression of receptors for B Lymphocyte Stimulator (BLyS, also known as BAFF), a cytokine critical for B cell maintenance, on B1b cells. In the context of polysaccharide immunization, TLR ligand administration may allow these antigen-specific B cells to more efficiently compete for limited BLyS and thus drive enhanced persistence and secondary responses. Our work may explain how TLRs function as adjuvants and also provide insights that will improve vaccination strategies. We have also found that in the absence of TLR2, B. hermsii-infected mice develop exaggerated bacteremia and die, displaying all of the histopathological and immunological characteristics of septic shock. We found that multiple intracellular sensors of bacteria are responsible for the induction of inflammation and the loss of NOD2, a cytoplasmic protein that detects bacterial peptidoglycan, significantly improves survival in TLR2-deficient mice. Our work highlights the redundancy of the innate immune system and may aid in the development of an effective immunomodulatory intervention strategy for septic patients by providing a more complete understanding of the myriad sensors of bacteria that cooperate to induce inflammation in sepsis.

Subject Area

Cellular biology|Immunology

Recommended Citation

Dickinson, Gregory S, "Determining the role of Toll-like receptors in innate and adaptive immune responses to Borrelia hermsii and other antigenic targets of T cell-independent humoral immunity" (2012). ETD Collection for Thomas Jefferson University. AAI3493707.
https://jdc.jefferson.edu/dissertations/AAI3493707

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