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ON THE ROLE OF CD24 IN THE PATHOGENICITY OF MYELIN ANTIGEN SPECIFIC T CELLS

Carl, Joseph William, Jr
http://rave.ohiolink.edu/etdc/view?acc_num=osu1210699484

Abstract Details

2008, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science.
CD24 is a glycosylphosphatidylinositol (GPI) anchored cell surface glycoprotein that is expressed in hematopoietic cells and cells of the central nervous system (CNS). Although CD24 is commonly used as a maturation marker for T lymphocytes, its role in thymocyte development is not clear. CD24 has been reported to function as a co-stimulatory molecule independent of CD28 and is required for the induction of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Bone marrow chimera experiments suggest that CD24 expression on both bone marrow-derived cells and CNS cells are required for EAE development. Studies of single nucleotide polymorphisms (SNPs) suggest that CD24 is related to the risk and progression of MS. We have used a series of genetic models to delineate the role of CD24 in the pathogenesis of EAE. It has previously shown that CD24 is required for the induction of EAE. In CD24-/- mice, normal levels of myelin oligodendrocyte glycoprotein (MOG) specific T cells were primed, however these T cells were non-pathogenic. To understand this issue, we bred CD24-/- mice with 2D2 TCR transgenic mice, which bear TCR specific to MOG, and generated 2D2 TCR transgenic mice with or without CD24. Here I show that 2D2 TCR transgenic mice with CD24-deficiency (2D2+CD24-/-) have remarkably withered thymi. In peripheral lymphoid organs, transgenic T cells from 2D2+CD24-/- mice have an immature phenotype (CD4-CD8-), do not respond to MOG peptide stimulation, and fail to cause autoimmune inflammation in the CNS and optical nerves. In contrast, OTII TCR transgenic mice with CD24 deficiency (OTII+CD24-/-), which bear TCR specific to chicken ovalbumin (OVA), have normal thymi and their peripheral T cells have a normal response to OVA peptide. These data suggest that CD24 inhibits thymic deletion of myelin antigen, but not foreign antigen-reactive T cells. To understand the role of CD24 on the resident cells in the CNS during EAE development, I created CD24 bone marrow chimeras and transgenic mice in which CD24 expressions was under the control of a glial fibrillary acidic protein promoter (GFAP) denoted AstroCD24. I showed that mice lacking CD24 expression on the CNS resident cells developed a mild form of EAE, but mice with over-expression of CD24 in the CNS developed severe EAE. Compared with nontransgenic mice, the CNS of AstroCD24 mice had higher expression of cytokine genes such as IL-17; the CNS of AstroCD24 mice accumulated higher numbers of Th17 and total CD4+ T cells, whereas CD4+ T cells underwent more proliferation during EAE development. Expression of CD24 in CD24-deficient astrocytes also enhanced their co-stimulatory activity to myelin oligodendrocyte glycoprotein-specific, TCR-transgenic 2D2 T cells. Thus, CD24 on the resident cells in the CNS enhances EAE development via co-stimulation of encephalitogenic T cells. The role of CD24 in the thymic generation and pathogenicity of myelin antigen specific T cells provides a novel explanation for its control of genetic susceptibility to autoimmune diseases in mice and humans.
Bai Xue-Feng, PhD (Advisor)
Caroline Whitacre, PhD (Committee Member)
Phillip Popovich, PhD (Committee Member)
James Waldman, PhD (Committee Member)
90 p.
Immunology
CD24; HSA; EAE; MS; Autoimmune; Thymus; Tolerance; 2D2;

Recommended Citations

Citations

  • Carl, Jr, J. W. (2008). ON THE ROLE OF CD24 IN THE PATHOGENICITY OF MYELIN ANTIGEN SPECIFIC T CELLS [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1210699484

    APA Style (7th edition)

  • Carl, Jr, Joseph. ON THE ROLE OF CD24 IN THE PATHOGENICITY OF MYELIN ANTIGEN SPECIFIC T CELLS. 2008. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1210699484.

    MLA Style (8th edition)

  • Carl, Jr, Joseph. "ON THE ROLE OF CD24 IN THE PATHOGENICITY OF MYELIN ANTIGEN SPECIFIC T CELLS." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1210699484

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.