Browsing by Subject "Mucosal immunology"

Dendritic cells (DCs) are potent antigen presenting cells (APC) that sense microbes and induce T cell activation and functional differentiation. The APC function of DCs is upregulated by the signaling pathway downstream of the microbial sensing receptor, a process well studied during pathogen infection and immunization. Multiple lines of evidence suggested that DCs in the intestine lamina propria (LP-DCs) frequently interact with the innocuous microbiota, and through these interactions LP-DCs support intestinal immune homeostasis. However, DC responses to microbiota, if not regulated, can give rise to inflammatory T cells and trigger inflammatory bowel disease (IBD). The DC subsets, DC functions and signaling pathways that induce inflammatory T cells remain incompletely characterized. Here, we demonstrated that mice lacking signaling attenuator A20 (A20cko mice) in DCs develop spontaneous small intestine inflammation that is dependent of microbiota, DCs and T cells. LP-DCs induce inflammatory T cells and that the signals perceived and APC functions are unique for three distinct LP-DC subsets. Thus, while CD103+CD11b- DCs exclusively upregulate their ability to instruct IFNγ+ T cells, CD103+CD11b+ DCs exclusively upregulate their ability to instruct IL-17+ T cells. Of note, APC functions of both DC subsets are upregulated in a MyD88-independent fashion. In contrast, CD103-CD11b+ DCs instruct both IFNγ+ and IL-17+ T cells, and only the IL-17-inducing APC functions require MyD88. In disease pathogenesis, both CD103-CD11b+ and CD103+CD11b+ DCs expand pathologic Th17 cells.

Although MyD88 pathways are potent inducer of intestinal inflammation in the colitis of IL-10 knockout mice and upon transferring of naïve T cells into Rag-deficient hosts, MyD88 pathways are not required for the inflammation of small intestine in A20cko mice. Among the MyD88-independent signaling pathways that could mediate host interaction with microbiota, Dectin-1 pathway is of particular interest because both the receptor Dectin-1 and the downstream signaling molecule CARD9 are IBD-associated genes. Additionally, the defect in either molecule influences the severity of the intestinal inflammation in mouse. We established that the production of inflammatory cytokines downstream of the Dectin-1 pathway is restricted by A20. Mechanistically, A20 inhibits TRAF6 ubiquitination downstream of the Dectin-1 pathway, thereby controlling NFκB and Jnk activation. Although we showed that CD103-CD11b+ and CD103+CD11b+ DCs express Dectin-1 and CARD9, the Dectin-1 pathway is not required for the upregulation of DC function and expansion of inflammatory T cells in the intestine of A20cko mice. Thus, our studies have unveiled a critical role of MyD88-independent pathways in mediating the interaction of the microbiota and LP-DCs. MyD88-independent pathway is capable of driving functional maturation of LP-DCs, pathological expansion of CD4 T cells, and the inflammatory disease in the small intestine.

The olfactory mucosa is a unique tissue because it directly connects the outside world to the central nervous system (CNS). From the apical side of the olfactory epithelium, olfactory sensory neurons (OSNs) extend their cilia directly into the airway. Simultaneously, their axons tunnel basolaterally through the skull and directly into the olfactory bulb of the brain. OSNs therefore serve as a single-cell bridge from the nasal airway to the CNS. The olfactory mucosa can therefore be considered an important mucosal barrier in two regards: it forms a component of the upper respiratory tract to defend against airborne pathogens, but it also must defend the brain from neurotropic microbes. At the same time, the olfactory mucosa must balance immune defense with tissue homeostasis and neuronal function to preserve the sense of smell. Despite these important roles, all of which relate to the immune system, the immune cells in this tissue have been woefully understudied. The purpose of this dissertation work is to characterize the immune barriers within the olfactory mucosa. This includes the first comprehensive characterization of hematopoietic cells in the olfactory mucosa, but also includes the first description of some important structural and stromal immune barriers in the tissue. The first chapter of this dissertation will review the plethora of olfactotropic pathogens, both neurotropic and otherwise, that impact the olfactory mucosa. Next, I will detail the methods I have developed to study and isolate tissue-resident immune cells of the olfactory mucosa. The third chapter will focus on the roles of macrophages in the olfactory tissue, describing for the first time two distinct subsets that contribute to neuronal maintenance and immune defense. The fourth chapter will highlight two important discoveries related to humoral defense of the olfactory mucosa. We describe for the first time the blood-olfactory barrier and mucosal plasma cells in the olfactory mucosa. Lastly, I will conclude by contextualizing these findings within the broader literature of upper airway immunity, giving the first encompassing review of olfactory immunity. Combined, the work in this dissertation will form an important building block for the field of olfactory immunology.