Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


osu1149171466.pdf (1.92 MB)

ETD Abstract Container

Abstract Header

X-Linked FOXP3 & OTC in immune tolerance and autoimmunity

Chang, Xing
http://rave.ohiolink.edu/etdc/view?acc_num=osu1149171466

Abstract Details

2006, Doctor of Philosophy, Ohio State University, Molecular, Cellular, and Developmental Biology.
Self and non-self discrimination is one of the fundamental tenets of immunology. For the immune system, to avoid devastating self constituents is as important as to respond effectively to evading pathogens. Failure of self tolerance often leads to autoimmune disease, in which the immune system is attacking and disrupting self tissues. Self tolerance is maintained by the discrimination of self antigens against non-self antigens. The main focus of this thesis is to study molecular and cellular mechanisms of self and non-self discrimination and how its failure leads to autoimmune disease. The thymus anatomically separates self antigens from non self antigens. Antigen expression in the thymus leads to the deletion of self-reactive T cells and generation of regulatory lymphocytes, including regulatory T cells(Treg) and NKT cells. Our data presented in Chapter 5 show an Ornithine transcarbamylase(OTC) mutation causes ineffective presentation of self antigens in the thymus. As such, deletion of self reactive T cells is compromised and introthymic production of Treg and NKT cells is reduced in the OTC mutant mice. More importantly the heterozygous mice have increased susceptibility to autoimmune diseases, including the generation of autoantibodies and more severe EAE induced by MOG immunization. Even with efficient introthymic deletion, some autoreactive T cells are still exported to the periphery. Another difference between self antigens and non self antigens is that the former are constantly expressed in the secondary lymphoid organs. High affinity interaction with antigens usually induces activation induced-cell death of reactive T cells. In Chaper 4, we present evidence that the activation induced cell death by high affinity self antigens is enhanced by regulatory T cells. By tracking endogenous superantigen reactive T cells in Scurfy mutant mice, which lack regulatory T cells altogether, we demonstrate that the absence of Treg causes the accumulation of autoreactive T cells in the periphery that evade normal clonal deletion in the thymus. Adoptive transfer experiments further reveal that Treg does not directly inhibit the proliferation of autoreactive T cells, but instead induce their programmed cell death. We also demonstrate that Treg mediated cytotoxity is specific to the autoreactive T cells, and such specificity is due to the higher sensitivity of autoreactive T cells to apoptosis. Although T cells with high affinity against self antigens can be eliminated from the repertoire, T cells with low affinities against self antigens are still unavoidable. Under physiological conditions, due to their low affinities those T cells are not able to be activated. However, in the lymphopenic environment, such low affinity interaction can drive T cell activation and expansion through homeostatic proliferation. In Chapter 2 and 3, we provide evidence that the FoxP3 gene mutation in Scurfy mice leads to reduced thymopoeisis and subsequently less T cell output from the thymus. The FoxP3 mutation in the thymic stroma causes defective T cell output from the thymus and lymphopenia in neonatal mice, which leads to extensive homeostatic proliferation that precedes antigen driven proliferation. The homeostatic proliferation is independent of the loss of Treg and FoxP3 mutation in the T cell lineage. We propose that the combined deficiency in T cell production and development of functional Treg may explain the severe autoimmunity associated with the FoxP3 mutation.
Yang Liu (Advisor)
Health Sciences, Immunology

Recommended Citations

Citations

  • Chang, X. (2006). X-Linked FOXP3 & OTC in immune tolerance and autoimmunity [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1149171466

    APA Style (7th edition)

  • Chang, Xing. X-Linked FOXP3 & OTC in immune tolerance and autoimmunity. 2006. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1149171466.

    MLA Style (8th edition)

  • Chang, Xing. "X-Linked FOXP3 & OTC in immune tolerance and autoimmunity." Doctoral dissertation, Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1149171466

    Chicago Manual of Style (17th edition)

osu1149171466
682
© 2006, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.