Document Type

Dissertation

Date of Degree

Summer 2014

Degree Name

PhD (Doctor of Philosophy)

Degree In

Immunology

First Advisor

John D. Colgan

Abstract

Tim-3 (for T cell immunoglobulin and mucin domain 3) is a surface molecule expressed throughout the immune system that appears to mediate both stimulatory and inhibitory effects. Tim-3 is expressed by activated CD4 and CD8 T cells, which suggests a direct role in the regulation of T cell responses. Consistent with this possibility, previous studies have shown that blockade of interactions between Tim-3 and ligands in the context of mouse models for autoimmunity and chronic infection can augment T cell responses, which indicates that Tim-3 functions as an inhibitory receptor for T cells. However, other studies have provided evidence that Tim-3 can function to promote T cell responses, which suggests that Tim-3 acts as a stimulatory receptor. In addition, biochemical and cell culture studies have shown that Tim-3 can induce both inhibitory and stimulatory signaling pathways. These conflicting findings highlight that the role of Tim-3 in regulating T cell responses remains unclear and warrants further investigation.

My studies sought to determine the role of Tim-3 in regulating T cell responses to microbial infections in vivo and to acute stimulation in vitro. Using Tim-3 KO mice and Tim-3 KO cells, I demonstrate that Tim-3 can directly enhance CD8 T cell responses to Listeria monocytogenes (LM). I also provide evidence that Tim-3 indirectly regulates CD4 T cell responses to LM. Alternatively, I show that Tim-3 may inhibit CD4 and CD8 T cell responses to the chronic viral infection LCMV-Clone 13, and that Tim-3 may be dispensable for T cell responses to the acute viral infection LCMV-Armstrong. Additionally, I demonstrate that Tim-3 expression in response to acute stimulation in vitro or in vivo marks populations of CD4 Th1 cells that are enriched for cells with effector function as measured by cytokine production and markers for degranulation. Collectively, these data suggest that Tim-3 may differentially regulate T cell effector function in a manner that is dependent on infectious environment encountered.

Pages

xiii, 149 pages

Bibliography

Includes bibliographical references (pages 130-149).

Comments

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Copyright

Copyright 2014 Jacob Vincent Gorman

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