Date of Award

2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Yasmine Belkaid

Abstract

Our body's epithelial surfaces are colonized by a diverse array of commensal organisms. While the contribution of intestinal commensals to metabolism, tissue development, and immunity has been extensively examined, the role of flora inhabiting other barrier sites in maintaining host physiology is poorly understood. Moreover, how resident commensals control unique physiological niches and the mechanisms underlying the host-microbial dialogue in distinct tissue sites requires elucidation. In Chapter 2 we find that murine skin, similar to human skin, houses unique commensal communities in topologically distinct niches. Furthermore, skin sites of both mice and non-human primates enriched with commensal niches contain more inflammatory T cells. Given that the skin forms a critical interface with the terrestrial environment and is an opportunistic site for pathogen entry, this tissue represents a highly relevant barrier site for studying the discrete interactions between resident immune cells and local flora outside the intestine.

The findings presented in Chapter 3 support a non-redundant role for the resident skin microbiota in setting the cutaneous inflammatory tone. More specifically, germ-free mice have an imbalance of effector and regulatory T cells in the skin that can be reversed upon addition of skin, but not gut, flora. Additionally, skin commensals act as natural adjuvants, boosting both protective immunity and pathology during Leishmania major infection. Thus, signals from the indigenous microbiota are necessary for optimal tissue immune fitness and function in the skin under steady state conditions and during infectious challenge.

In Chapter 4, we identify the interleukin-1 receptor (IL-1R1) as an essential regulator of cutaneous T cell function. Accordingly, mice deficient in IL-1R1 and its downstream signaling adaptor, Myd88, recapitulate the homeostatic and immune defects observed in the skin of germ-free mice. Emphasizing the partitioning of innate signals in the skin and gut, IL-1 signaling is dispensable for intestinal T cell function. Importantly, cutaneous commensals locally amplify IL-1/MyD88, signaling to tune the function of effector T cells in the dermis. Taken together, these studies underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization and provide insight into the mechanisms of immune regulation by resident commensal niches in health and disease.

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