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Publication Date

2016-12-19

Availability

UM campus only

Embargo Period

2016-12-19

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2016-11-29

First Committee Member

Zhibin Chen

Second Committee Member

Rebecca Adkins

Third Committee Member

Maria Abreu

Fourth Committee Member

Gregory Plano

Fifth Committee Member

Ralf Landgraf

Sixth Committee Member

Kenneth Murphy

Abstract

The gut microbiota is an important symbiotic contributor to human health. They provide essential nutrients and prevent colonization by pathogenic bacteria. Furthermore, the gut microbiota provides the signals for proper development of the immune system. How the adaptive immune system, specifically the T cell lineage, tolerates the gut microbiota remains a question. Specific antigen based tolerance would be problematic since both pathogenic bacteria and their microbiota counterparts differ minimally. Given the evidence from numerous studies on T cell differentiation induced by gut bacteria, it is possible that the gut environment may induce mechanisms of T cell plasticity that is not constrained by the notion of “self” versus “nonself” recognition. I hypothesize that T cell clones in the gut environment can differentiate at steady state to facilitate immune balance independent of “self” or “nonself” T cell receptor specificity. By using mouse models of single T cell clones specific for “self” and “nonself” antigen in the CD4 and CD8 lineage, I identified a mechanism of lineage plasticity whereby CD8+ T cells become CD4+ T cells restricted to Major Histocompatibility Complex Class I. These differentiated CD4+ T cells controlled CD8+ T cell homeostasis and suppressed colitis. Although cross-differentiation of CD8+ T cells to CD4+ T cells occurrs in a host intrinsic manner, microbiota may serve as a signal for expansion or homing of cross-differentiated MHC Class-I-restricted CD4+ T cells and Foxp3+ T regulatory cells. The discovery of these cells may have implications in autoimmunity, HIV infection, and cancer.

Keywords

immune tolerance; lineage plasticity; T cells; Treg; lamina propria; microbiota

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