Over time, the immune system evolved to combat pathogens encountered in ever-changing environments. Early jawless vertebrates possess T-like cells that develop in a thymus-like structure. However, more sophisticated jawed vertebrates evolved complex immune systems consisting of an "innate" arm and an "adaptive" arm. It is this adaptive arm that is responsible for combating infections such as viruses and bacteria. In order to achieve broad specificity for newly encountered pathogens, the adaptive immune system must generate an immense variation of antigen receptors. Unfortunately, this diverse array of receptors carries varying specificities, including many receptors that recognize self-antigens with high affinity. The process of distinguishing between foreign- and self-antigens, termed immune tolerance, is accomplished in two modes: central and peripheral. Central tolerance is achieved during B and T cell development in the bone marrow and thymus, respectively, whereas peripheral tolerance occurs after B and T cells mature and enter the periphery.

Central tolerization of T cells is achieved in a series of maturation and selection steps starting with a T cell precursor, the thymocyte, and ending with a naïve T cell bearing a matured T cell receptor ready to combat pathogens (Figure 1).

Figure 1. Maturation of T cell precursors in the thymus

Central tolerance consists of two processes: The first, negative selection, assures thymocytes bearing TCRs that bind self-peptide: MHC with high affinity die by apoptosis. One of the primary focuses of the Hsieh Lab has been the second process, thymic Treg selection. The lab has shown that thymic Treg development is an instructive process that can occur in a two-step process (Figure 2) within a resource-limited niche.

Figure 2. Two-step model of thymus-derived Treg development

I focus on the first step of thymic Treg development. In the thymic medulla, several cells exist capable of presenting antigen through MHC-II. Previous work using transgenic TCR models provides mixed results. It remains unclear what role the various dendritic cell populations and medullary thymic epithelial cells (mTECs) play in thymic Treg selection. Therefore I am working to elucidate the specific contributions of individual antigen presenting cells (APCs) to Treg cell and negative selection. The lab specializes in TCR sequencing and I plan to use this technique to assist in determining such roles of APCs via various mouse models. Through the combination of cellular and molecular techniques, I hope to better understand the thymic Treg selecting niche.

We recently showed that BM APCs and mTECs select non-redundant T cell TCR repertoires. Furthermore, we show that Aire is necessary for Treg cell and negative selection of a substantial portion of the TCR repertoire. Importantly, we show that Aire equally mediates selection through autologous presentation by mTECs and antigen transfer to BM APCs. We demonstrate that Treg cell selection via this process depends on CD8a+ DCs (Figure 3: Immunity, Volume 41, Issue 3, p414–426, 18 September 2014). For a preview of our work, see Kyewski and Feuerer (p343-345).

Figure 3: Distinct Contributions of Aire and Antigen-Presenting-Cell Subsets to the Generation of Self-Tolerance in the Thymus.