Maintaining Tolerance to Nucleic Acids and the Microbiota Early in Life
- Author(s): Stanbery, Alison Gayle
- Advisor(s): Barton, Gregory
- et al.
Throughout life the immune system is faced with the challenging task of appropriately responding to both self- and nonself-derived ligands. The innate immune system utilizes pattern-recognition receptors, such as Toll-like receptors (TLR), to identify specific features of microbes, while the adaptive immune system employs T cells and antibodies (IgA, IgG) to generate robust secondary responses to invasive microorganisms. However, this poses the potential for inappropriate recognition of self-derived ligands or symbiotic bacteria. Therefore, the balance between recognition of non-self while preserving tolerance to self is necessary to prevent autoimmunity and detrimental infections. To better understand this balance, I first examined how the innate immune system prevents recognition of self-nucleic acids. In this study, I explored the consequences of dysregulating compartmentalized activation of a nucleic acid sensing receptor, TLR9. By inducing in vivo expression of a TLR9 mutant (TLR9TM) that bypasses the need for intracellular activation, I discovered that dysregulated TLR9 activation early in life drives a fatal inflammatory disease, driven by type II interferon. In contrast, induced expression of TLR9TM late in life led to a milder, systemic autoinflammatory disease. This study demonstrates that compartmentalized activation of TLR9, especially early in life, is necessary to prevent deleterious recognition of self-nucleic acids.
Early in life the naïve immune system must be able to differentiate pathogenic microbes from symbiotic, beneficial microbes. The naïve immune system receives some instruction through acquisition of maternal-derived microbiota-reactive antibodies, such as IgG2b and IgG3. These antibodies are anti-inflammatory and help to suppress inappropriate immune responses to commensal bacteria in the neonatal gut. However, the exact mechanism(s) by which maternal-derived IgG2b and IgG3 instruct the naïve immune system remain relatively unknown. To better understand the role of microbiota-reactive IgGs in tuning the immature immune system, I generated mice that produce pro-inflammatory microbiota-reactive IgG2c (termed IgG32c/2c mice). Examination of the IgG32c/2c mice revealed that acquisition of maternal-derived microbiota-reactive IgG2c leads to fatal disease. This disease was characterized by weight loss and intestinal inflammation as measured by an increase in fecal lipocalin-2, an increase in intestinal myeloperoxidase, and an expansion of CD11b+ myeloid cells in the spleen. In contrast, neonates that acquire maternal-derived microbiota-reactive IgG3 do not experience weight loss, inflammation, or fatality. This study establishes that effector functions elicited by maternal-derived microbiota-reactive antibodies help dictate neonatal fitness by fine-tuning the responses generated by the naïve immune system to symbiotic gut bacteria.
The work in this dissertation establishes how the innate immune system regulates nucleic-acid sensing TLRs to prevent inappropriate recognition of self-derived ligands. In addition, the work in this dissertation reveals how maternal-derived antibodies instruct the naïve immune system in how to respond to beneficial microbes early in life.