Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


ucin1266607502.pdf (3.83 MB)

ETD Abstract Container

Abstract Header

The Role Of Chemokines and Dendritic Cells In Regulation of IL-4 and Fungal Immunity

Szymczak, Wendy A.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1266607502

Abstract Details

2010, PhD, University of Cincinnati, Medicine : Molecular Genetics, Biochemistry, and Microbiology.
Histoplasma capsulatum is a dimorphic fungus that can cause lethal infection in immunocompromised hosts. In order to resolve infection, the host must mount a TH1 immune response that is accompanied by an influx of inflammatory cells to the primary site of infection, the lung. Chemokines regulate cell recruitment and TH1/TH2 polarization; however, the role of chemokines in control of H. capsulatum infection has not been explored. We have demonstrated that the chemokine receptor CCR2 is requisite for protective immunity to H. capsulatum. H. capsulatum infected CCR2-/- mice manifested defects in inflammatory cell recruitment, increased interleukin (IL)-4, and progressive infection. Increased IL-4 in CCR2-/- mice diminished host resistance as demonstrated by the ability of IL-4-neutralized CCR2-/- mice to resolve infection without altering cell recruitment. In contrast, mice lacking CCL2, a major CCR2 ligand, did not exhibit elevated IL-4 and resolved infection. Lack of both CCL2 and the CCR2 ligand CCL7 produced a phenotype similar to that observed in CCR2-/- mice demonstrating for the first time that CCL2 and CCL7 mutually regulate IL-4. We examined the cellular sources that contributed to IL-4 production in lungs of CCR2-/- mice. Surprisingly, numerous alveolar macrophages and dendritic cells (DC) secreted IL-4 in addition to CD4+ T cells at the peak of infection. We explored the mechanism by which IL-4 exacerbated infection. Elevations of IL-4 in CCR2-/- mice were associated with alternatively activated Mϕ which exhibited increased arginase-1. Administration of L-arginine, an arginase-1 substrate, or BEC ((S)-(2-Boronoethyl)-L-cysteine, HCl), an arginase-1 inhibitor, partially decreased fungal burden in CCR2-/- mice indicating that increased arginase-1 expression is deleterious to host defense. We investigated the mechanism by which IL-4 becomes elevated in lungs of CCR2-/- mice. Infected CCR2-/- or CCL2-CCL7 deficient mice exhibited a marked decrement in the number of CD8- conventional DC in lungs, therefore we hypothesized that these cells restrict IL-4 generation. Adoptive transfer of antigen (Ag)-loaded WT bone marrow-derived DC (Ag-BMDC) to WT or CCR2-/- mice resulted in suppression of IL-4 whereas adoptive transfer of BMDC that were not exposed to Ag had no effect. Transfer of Ag-BMDC lacking CCR2 also limited IL-4 generation. We asked if DC-mediated MHCII-Ag presentation to CD4+T cells was necessary for IL-4 restriction. MHCII-/- Ag-BMDC did not limit IL-4 when transferred to CCR2-/- mice and depletion of CD4+ T cells prior to, but not at the initiation of infection, resulted in decreased IL-4 indicating that Ag-BMDC suppression of IL-4 is dependent on limiting production by CD4+ T cells early during infection. Fungal burden was not reduced in CD4-depleted CCR2-/- mice but CCR2-/- mice that received Ag-BMDC in addition to depletion of CD4+ T cells were able to control infection. Together, the data suggest that elevated IL-4 in CCR2-/- mice arises from decreased recruitment of DC capable of presenting antigen. Furthermore, CD4+ T cells dampen immunity in H. capsulatum infected-CCR2-/- mice.
George Deepe, MD (Committee Chair)
Alison Weiss, PhD (Committee Member)
Rodney Dekoter, PhD (Committee Member)
James Stringer, PhD (Committee Member)
Edmund Choi, PhD (Committee Member)
140 p.
Microbiology
fungi; chemokine; IL-4; host immune response; CCR2; TH1 TH2

Recommended Citations

Citations

  • Szymczak, W. A. (2010). The Role Of Chemokines and Dendritic Cells In Regulation of IL-4 and Fungal Immunity [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1266607502

    APA Style (7th edition)

  • Szymczak, Wendy. The Role Of Chemokines and Dendritic Cells In Regulation of IL-4 and Fungal Immunity. 2010. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1266607502.

    MLA Style (8th edition)

  • Szymczak, Wendy. "The Role Of Chemokines and Dendritic Cells In Regulation of IL-4 and Fungal Immunity." Doctoral dissertation, University of Cincinnati, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1266607502

    Chicago Manual of Style (17th edition)

ucin1266607502
474
© 2009, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.