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Effects of Toll-Like Receptors and Type I Interferon on Dendritic Cell Maturation and Activation of T Cells

Simmons, Daimon P.
http://rave.ohiolink.edu/etdc/view?acc_num=case1311278278

Abstract Details

2011, Doctor of Philosophy, Case Western Reserve University, Pathology.
Early responses triggered by innate immune activation determine the ultimate host response to infection, including the presence or absence of long-lived adaptive immunity. Dendritic cells (DCs) are the sentinels of the immune system that recognize foreign material through Toll-like receptors (TLRs) and respond by maturing, migrating to lymph nodes, and processing and presenting antigen to activate naïve T cells. Exogenous antigen is processed and presented by class II major histocompatibility (MHC-II) molecules to CD4+ T cells, and endogenous antigen is processed and presented by class I major histocompatibility (MHC-I) molecules to CD8+ T cells. DCs can also cross process and present exogenous antigen by MHC-I to activate CD8+ T cells that recognize antigens not endogenously synthesized by DCs. The combination of innate receptors triggered on DCs determines the ultimate immune response. TLR9 agonists induce the production of Type I IFN (IFN-α/β), while agonists of other receptors such as TLR2 do not. IFN-α/β strongly upregulates cross processing in DCs and enhances CD8+ responses. IFN-α/β alone can induce maturation of DCs, and it can also shape DC responses in conjunction with TLR agonists. We report that M. tuberculosis (Mtb), a bacterial pathogen that expresses agonists of both TLR2 and TLR9, suppresses the induction of IFN-α/β. TLR2 agonists inhibit TLR9 induction of IFN-α/β, and Mtb inhibits TLR9 induction of IFN-α/β at least partially through TLR2. Mtb also inhibits cross processing and presentation of mycobacterial antigen by inhibiting induction of IFN-α/β, thereby potentially limiting CD8+ responses. We also report that DC maturation induced by TLR agonists results in decreased subsequent MHC-II processing, while MHC-II processing is maintained after maturation driven by IFN-α/β. When DC maturation is induced by IFN-α/β, MHC-II mRNA and CIITA mRNA is maintained; and MHC-II is expressed both in vacuoles and on the cell surface, consistent with a phenotype that allows continued MHC-II processing. IFN-α/β modulates antigen processing by both MHC-I and MHC-II in DCs, and the environment of TLR agonists and cytokines can ultimately determine the difference between protective immunity and autoimmunity.
Clifford Harding, MD PhD (Advisor)
Alan Levine, PhD (Committee Chair)
Henry Boom, MD (Advisor)
David Canaday, MD (Committee Member)
Carlos Subauste, MD (Committee Member)
Clive Hamlin, MD (Committee Member)
160 p.
Immunology
Tuberculosis; interferon; antigen processing; antigen presentation; dendritic cells

Recommended Citations

Citations

  • Simmons, D. P. (2011). Effects of Toll-Like Receptors and Type I Interferon on Dendritic Cell Maturation and Activation of T Cells [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1311278278

    APA Style (7th edition)

  • Simmons, Daimon. Effects of Toll-Like Receptors and Type I Interferon on Dendritic Cell Maturation and Activation of T Cells. 2011. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1311278278.

    MLA Style (8th edition)

  • Simmons, Daimon. "Effects of Toll-Like Receptors and Type I Interferon on Dendritic Cell Maturation and Activation of T Cells." Doctoral dissertation, Case Western Reserve University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1311278278

    Chicago Manual of Style (17th edition)

case1311278278
560
© 2011, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.