Degree Type

Dissertation

Date of Award

2006

Degree Name

Doctor of Philosophy

Department

Veterinary Microbiology and Preventive Medicine

First Advisor

Douglas E. Jones

Abstract

Cutaneous leishmaniasis is a vector-borne disease caused by intracellular protozoan parasites of the genus Leishmania. C3H mice challenged with L. major develop a polarized Th1 response and subsequently heal, whereas L. amazonensis challenge leads to chronic lesions with high parasite loads. This work demonstrates that infection with L. amazonensis creates a population of antigen-responsive, CD44hi CD4+ T cells that proliferate and produce IL-2 but do not polarize to an effector phenotype and exhibit limited IFN-gamma production in response to IL-12. CD44 hi CD4+ T cells from L. amazonensis-infected mice fail to accumulate in culture as compared to cells from L. major -infected mice. Neutralization of IL-2 promotes IL-12-mediated enhanced proliferation of CD44hi CD4+ T cells from L. amazonensis-infected mice, indicating that IL-2 limits cell accumulation in response to IL-12 in vitro. Following multiple antigen stimulations, CD44 hi CD4+ T cells from L. amazonensis-infected mice sustain higher CD25 expression than cells from L. major-infected mice, a phenotype regulated by IL-2 and similar to regulatory T cells. To recapitulate continual in vitro culture of CD4+ T cells with IL-12 in vivo, multiple doses of IL-12 were administered to mice during the first two weeks of L. amazonensis infection. Although mice administered IL-12 developed a Th1 response early during infection, that response was not maintained and the mice failed to heal their infections. IL-12 treatment also failed to promote a sustained source of antigen-specific IL-12 from B cells in these mice, indicating that the failure of IL-12-treated L. amazonensis-infected mice to heal their infection is not due to an inability to mount a Th1 response, but rather from a lack of sustained, antigen-specific IL-12 production from B cells. Together, these results indicate that although CD4+ T cells from L. amazonensis-infected mice respond to IL-12 by enhancing IFN-gamma production, IL-2 suppresses their ability to enhance proliferation in response to IL-12. We believe this incomplete IL-12 responsiveness contributes to the chronicity of L. amazonensis infection.

DOI

https://doi.org/10.31274/rtd-180813-11512

Publisher

Digital Repository @ Iowa State University, http://lib.dr.iastate.edu

Copyright Owner

Amanda Ellen Ramer

Language

en

Proquest ID

AAI3217306

File Format

application/pdf

File Size

143 pages

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