Dendritic cell NFkB function in T cell activation and autoimmunity

Thompson, Angus Gordon. (2004). Dendritic cell NFkB function in T cell activation and autoimmunity PhD Thesis, School of Medicine, The University of Queensland.

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Author Thompson, Angus Gordon.
Thesis Title Dendritic cell NFkB function in T cell activation and autoimmunity
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2004
Thesis type PhD Thesis
Supervisor Professor Ranjeny Thomas
Professor Ian Frazer
Total pages 191
Collection year 2004
Language eng
Subjects L
300504 Immunology
730102 Immune system and allergy
Formatted abstract

Dendritic cells (DC) play a key role in the control of the immune response. This is achieved by the presentation of antigen to T cells, secretion of cytokines and the modulation of costimulatory molecules dependent upon the cellular and molecular environment in which the antigen is presented. DC influence peripheral tolerance both constitutively and in inflammation, in order to prevent autoimmunity and to control established immune responses. Various factors may determine the outcome of the interaction between a DC and other cells of the immune system. The elucidation of the biochemical signaling pathways that control DC function and differentiation provides important insights into control mechanisms in immunity. This thesis examines the role of the NFκB family of transcription factors in DC function and the impact of NFκB inhibition on T cell activation. Differentiated DC have been identified by the presence of nuclear Re1B (nRe1B) and HLA-DR, and the absence of CD20 or high levels of CD68, in lymph nodes and active rheumatoid arthritis synovial tissue. Normal peripheral tissue did not contain nRe1B+ cells. nRe1B+ DC were located only in T or B cell areas of lymphoid tissue associated with normal organs or peripheral tissues, including tonsil, colon, spleen and thymus, or in association with T cells in inflamed peripheral tissue. nRe1B+HLA-DR- follicular DC were located in B cell follicles in lymphoid organs, and in lymphoid-like follicles of some tissues affected by autoimmune disease. Lymphoid tissue T cell areas also contained nRe1B-HLA-DR+ cells, some of which expressed CD 123 and/or CD68. Therefore, nRe1B+ cells are found in normal lymphoid organs and in peripheral tissue in the context of inflammation, but not under normal resting conditions. In vitro, CD40- human monocyte-derived dendritic cells, generated in the presence of an NFκB inhibitor (Bay-treated DC), signaled low levels of T cell proliferation and interferon (IFN)y production. Surprisingly, in contrast to in vivo studies of CD40- DC, T cells responding to Bay-treated DC were neither anergic nor regulatory, but were sensitized for subsequent IFNy production upon restimulation either mitogen or mature DC. Based on these observations, it was hypothesized that factors secreted or expressed by DC are responsible for the failure of T cells to enter the cell cycle and proliferate, through a lack of available T cell growth factors. Indoleamine 2,3 dioxygenase (IDO) - an inhibitor of tryptophan catabolism, nitric oxide - associated with suppressor antigen presenting cells (APC), and IL-10 were not responsible for the lack of proliferation, and cytokine production by Bay-freated DC. Addition of EL-12 or IL-1 was unable to restore the proliferation of T cells in response to Bay-freated DC, but IL-2 enhanced T cell proliferation in response to Bay-freated DC in a dose dependent manner. The data indicate that signaling through NFκB determines the capacity of DC to stimulate T cell IL-2 production sufficient for entry of T cells into the cell cycle. Functionally, NFκB- CD40-MHC class II+ DC may either tolerize or sensitize T cells. Thus, while CD40- DC appear to "prime" or prepare T cells, the data imply that signals derived from other cells drive the generation either of antigen-specific regulatory or effector cells in vivo. 

Keyword Dendritic cells -- Therapeutic use
T cells

Document type: Thesis
Collection: UQ Theses (RHD) - UQ staff and students only
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Created: Fri, 24 Aug 2007, 18:34:48 EST