Publication Date

2012-08-21

Availability

Embargoed

Embargo Period

2013-08-21

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2012-04-24

First Committee Member

Thomas R. Malek

Second Committee Member

Richard L. Riley

Third Committee Member

Robert B. Levy

Fourth Committee Member

Alberto Pugliese

Fifth Committee Member

Jacob McCauley

Sixth Committee Member

Abul K. Abbas

Abstract

CD4+ Foxp3+ regulatory T (Treg) cells belong to a distinct T cell lineage which develops in the thymus and is essential for the prevention of self-reactivity by suppressing peripheral auto-reactive T cells that escape thymic negative selection. IL-2/IL-2R signaling is crucial and non-redundant for the development of thymic Treg cells, as well as the homeostasis and competitive fitness of peripheral Treg cells. The central role of IL-2 in Treg biology is exemplified by the uncontrolled massive lymphoproliferation associated with IL-2-/-, IL-2Rα-/- and IL-2Rβ-/- mice which typically die by 4-12 week of age. It is noteworthy that a restored normal percentage and number of peripheral Treg cells in Bim-/- IL-2-/- mice did not rescue these mice from severe autoimmunity. Instead, additional IL-2 was still required for the proper functioning of peripheral Bim-/- IL-2-/- Treg cells. Consistently, in the current studies, we found that the development of thymic Treg cells was blocked with mostly CD4+ CD25- Foxp3lo T cells in the IL-2Rβ-/- mice, and these cells were mainly defective for functional maturation. However, weak IL-2Rβ signaling associated with IL-2Rβ mutant mice largely supported normal Treg development and function in the thymus. Further examination indicated that the contribution of this weak IL-2Rβ signaling was associated with pSTAT5 activity. Although low IL-2 signaling is sufficient for programming mature and functional thymic Treg cells prior to their populating the periphery, aged IL-2Rβ mutant mice bearing weak and transient pSTAT5 signal develop autoimmunity by involving T cell infiltration into tissue sites. In addition, gene array analysis of peripheral Treg cells with lower IL-2R signaling suggested that the expression of some molecules is IL-2 dependent, such as Klrg1. We found that Klrg1 marked a small fraction of peripheral Treg cells. They were highly activated, antigen-responsive and short-lived. Klrg1+ Treg cells were also potentiated with superior suppressive function and represented a terminally differentiated subset derived from Klrg1- Treg precursors. Importantly, the development of Klrg1+ Treg subset required extensive IL-2R signaling. This activity of IL-2 is distinct from its contribution to Treg homeostasis and competitive fitness. Overall, these properties are analogous to Klrg1 marked terminally differentiated short-lived CD8+ T effector cells. Thus, a pathway driving antigen activated conventional T lymphocytes is also similarly co-operated by Treg cells.

Keywords

IL-2R; T regulatory cells; T cell subset; autoimmunity; Klrg1; Thymic development

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