Naturally occurring Foxp3+ regulatory T (Treg) cells play an important role in the maintenance of immune homeostasis and prevention of autoimmunity. Although it is commonly thought that self-reactivity is important for Treg cell selection, the quantitative parameters that govern this process has not been reported. In this proposal, we will analyze the role of TCR self-reactivity in thymic Treg cell differentiation as wel as negative selection.
In Aim 1, we will study these thymic tolerance mechanisms using a novel panel of TCRs with broad reactivity to ovalbumin peptide (OVA323-339). If self-reactivity is the primary driving force for thymic Treg cell development as suggested by our preliminary data, then the antigens presented in the thymus will determine the Treg cell repertoire.
In Aim 2, we will address whether the thymic APC subsets serve non-redundant capacities in Treg cell generation and negative selection. Finally, we will assess in Aim 3 whether the level of self-reactivity that triggers thymic tolerance mechanisms also triggers peripheral Treg cell generation. We will also assess the degree of self-reactivity needed for Treg cells to prevent autoimmunity, as well as for effector cells to cause pathology. Understanding the mechanisms that govern Treg cell development may lead to the development of therapies which utilize Treg cell-mediated therapies for the treatment of autoimmune disease.
Regulatory T cells are a subset of immune cells which are potent inhibitors of immune inflammation. Their normal role is to prevent the spontaneous development of autoimmune disease. Our goal is to understand the mechanisms by which regulatory T cell normally develop, with the notion that this information can help in the design of therapies which enhance the generation of regulatory T cells to treat autoimmune disease.
|Perry, Justin S A; Hsieh, Chyi-Song (2016) Development of T-cell tolerance utilizes both cell-autonomous and cooperative presentation of self-antigen. Immunol Rev 271:141-55|
|Ai, Teresa L; Solomon, Benjamin D; Hsieh, Chyi-Song (2014) T-cell selection and intestinal homeostasis. Immunol Rev 259:60-74|
|Perry, Justin S A; Lio, Chan-Wang J; Kau, Andrew L et al. (2014) Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41:414-26|
|Nutsch, Katherine M; Hsieh, Chyi-Song (2012) T cell tolerance and immunity to commensal bacteria. Curr Opin Immunol 24:385-91|
|Hsieh, Chyi-Song; Lee, Hyang-Mi; Lio, Chan-Wang J (2012) Selection of regulatory T cells in the thymus. Nat Rev Immunol 12:157-67|
|Lee, Hyang-Mi; Bautista, Jhoanne L; Scott-Browne, James et al. (2012) A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. Immunity 37:475-86|
|Lathrop, Stephanie K; Bloom, Seth M; Rao, Sindhuja M et al. (2011) Peripheral education of the immune system by colonic commensal microbiota. Nature 478:250-4|
|Lio, Chan-Wang J; Hsieh, Chyi-Song (2011) Becoming self-aware: the thymic education of regulatory T cells. Curr Opin Immunol 23:213-9|
|Lio, Chan-Wang J; Dodson, Lindzy F; Deppong, Christine M et al. (2010) CD28 facilitates the generation of Foxp3(-) cytokine responsive regulatory T cell precursors. J Immunol 184:6007-13|
|Bautista, Jhoanne L; Lio, Chan-Wang J; Lathrop, Stephanie K et al. (2009) Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat Immunol 10:610-7|
Showing the most recent 10 out of 11 publications