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Title

Cellular and Molecular Characterization of Thymic Regulatory T cell Development

Date of Award

Summer 8-15-2011

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

A hallmark of adaptive immunity is the ability to recognize an enormous diversity of foreign antigens. However, the inevitable consequence of a diverse antigen receptor repertoire is the inappropriate recognition of self-antigens, which can cause autoimmune disease. To avoid this scenario, thymocytes, after rearranging their T cell receptors (TCRs), interact extensively with the thymic antigen presenting cells (APCs) to purge the self-reactive cells by clonal deletion. Alternatively, a portion of self-reactive thymocytes is deviated as Foxp3+ regulatory T (Treg) cells. Although it is well established that Treg cells are important for preventing spontaneous autoimmunity, the mechanisms by which they develop remained unclear. In this study, we sought to understand the developmental process with an initial focus on the cellular pathways. We found that the thymic Foxp3­ CD4SP CD25hi subset is enriched in Treg cell precursors. Subsequent acquisition of IL-2 and/or IL-15 signal is sufficient to induce Foxp3 in the absence of further TCR engagement. These data suggest that the Treg cell development operates as a two-step process. Taking advantage of the discovery of Treg cell precursors, we found that the generation of these cells requires CD28 signals which can be partially attributed to the Lck-binding PYAP motif within the CD28 tail. Furthermore, the Treg cell TCR repertoire that developed in the absence or presence of CD28 was largely similar, suggesting that CD28 facilitates the TCR-instructed development of Treg cell precursor. Since both CD80/CD86, ligands for CD28, and peptide/MHC are expressed on the surface of APCs, we next focused on studying the role of medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), the two major thymic APCs, in supporting Treg cell development. We found that mTECs and DCs potentially have overlapping but also unique contributions for selecting thymic Treg cells. In summary, we showed that thymocytes interact with multiple APCs to screen for self-reactive TCRs. If the TCRs have a relatively high avidity for self-antigens in the presence of CD28 signal, the thymocytes can be selected as Foxp3­ CD25hi Treg cell precursors. Upon receiving the cytokine signal by IL-2, these precursor cells will then express Foxp3 and mature into Treg cells.

Language

English (en)

Chair and Committee

Chyi-Song Hsieh

Committee Members

Paul Allen, Takeshi Egawa, Kenneth Murphy, Wojciech Swat, Emil Unanue, Wayne Yokoyama

Comments

Permanent URL: https://doi.org/10.7936/K7XS5S90

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