Laura Tesmer
e-mail address: ltesmer@umich.edu

Mentor: David Fox, MD

Research Description

CD4+ T helper cells are typically thought to differentiate into two effector subclasses: Th1, characterized by the production of gamma IFN, and Th2, characterized by the production of IL-4. A new class of T helper cell has recently been described, designated Th17. Th17 cells are characterized by the production of IL-17 but not gamma IFN or IL-4. IL-17 is an extremely potent pro-inflammatory cytokine that has been shown to be important in several mouse models of autoimmunity. Notably, blocking or knocking out IL-17 significantly reduced the onset and severity of collagen-induced arthritis, while adding back IL-17 exacerbated inflammation and joint destruction. Specific inhibition of IL-17 production or activity is quickly becoming a therapeutic goal for the treatment of several immunopathologies, including rheumatoid arthritis. Th17 development has been shown to be inhibited by Th1 and Th2 cytokines, including IL-12, gamma IFN, and IL-4. We have observed a strong downregulation of IL-17 production by IL-4 during ex vivo antigen rechallenge of spleen cells from mice with collagen-induced arthritis. Interestingly, however, Th17 cells from end-stage arthritis or long term culture are no longer susceptible to downregulation by IL-4, suggestive of maturation of the Th17 phenotype. We are currently working to understand the signals involved in the maturation of Th17 cells from an IL-4-sensitive to an IL-4-resistant state as well as the underlying mechanism for the loss of IL-4 responsiveness. We also hope to determine what role Th17 maturation plays in the development and progression of arthritis.

Publications

Sarkar S, Tesmer LA, Hindnavis V, Endres JL, and Fox DA: IL-17 as a Molecular Target in Immune-Mediated Arthritis - Immunoregulatory Properties of Genetically-Modified Dendritic Cells that Secrete IL-4. Arthritis and Rheumatism, 2007, 56(1):89-100.

Tran CN, Davis MJ, Tesmer LA, Endres JL, Motyl CD, Smuda C, Somers EC, Chung KC, Urquhart AG, Lundy SK, Kovats S and Fox DA: Presentation of Arthritogenic Peptide to Antigen Specific T cells by Fibroblast-Like Synoviocytes. Arthritis and Rheumatism. 2007, 56(5):1497-506.

3. Lundy SK, Sarkar S, Tesmer LA, and Fox DA: Cells of the Synovium in Rheumatoid Arthritis: T lymphocytes. Arthritis Res. Ther. 2007, 9(1):202.

4. Lu Q, Wu A, Tesmer L, Ray D, Yousif N, and Richardson B: Demethylation of CD40LG on the Inactive X in Women with Lupus. PNAS in press 2007.

5. MacGregor JN, Kryczek I, Tesmer LA, Fox DA, Zou W, and King PD: Characterization of Regulatory T cells and T helper-17 T cell Development in Autoimmune-Prone Mice Lacking the T Cell-Specific Adapter Protein. In preparation.

Abstracts

Tesmer LA , Sarkar S, and Fox DA: Regulation of IL-17 Production During Antigen-Specific Responses in the Mouse. AAI annual meeting, 2006.

Tesmer LA , Sarkar S, and Fox DA: Regulation of IL-17 Production by Th1 and Th2 Cytokines During Collagen-Induced Arthritis. American College of Rheumatology annual meeting, 2006.