Chlamydia trachomatis, an obligate intracellular bacterium, causes the most cases of bacterial sexually transmitted infections (STIs). Three million new cases of infection occur in the US each year and commonly result in pelvic inflammatory disease (PID), ectopic pregnancy and tubal infertility which costs the health care industry billions of dollars annually. Regulatory T cells (Tregs) have the ability to suppress T cell responses and prevent host tissue inflammation. Devising a means for limiting inflammation in the upper genital tract (UGT) would likely prevent the sequelae that follow chlamydial infection. We have identified CD4+FoxP3+Tregs and CD8+CXCR5+Tregs that appear in overlapping but different locations during chlamydial genital infection and likely influence infection by distinct means. Our preliminary data indicates that CD4+FoxP3+Tregs are present during infection in the genital tract and secondary lymphoid tissue. Reduction in the number of pDC alters the balance of Th1/Tregs during chlamydial genital infection and suggests that pDC are involved in production of CD4+FoxP3+Tregs. In contrast, CD8+CXCR5+Tregs cells are present in naove mice prior to infection. The lack of CD8+CXCR5+Tregs result in marked lymphocyte accumulation and collagen deposition surrounding oviducts after chlamydial infection. Infection stimulates Tregs function by inducing the expression of FoxP3, regulating cytokine secretion by MoPn-responsive T cells in vivo and reversing lymphocyte accumulation and collagen deposition in the UGT. Taken together, we hypothesize that FoxP3+Tregs regulate chlamydial infection and UGT tissue inflammation and propose the following specific aims: 1. Identify mechanism(s) by which CD8+CXCR5+ Tregs control chlamydial genital infection. 2. Evaluate the contribution of CD4+FoxP3+Tregs on Chlamydia genital infection. We will test these Aims with in vivo and in vitro experiments of genital infection with the mouse agent of C. trachomatis (MoPn), adoptive transfer, flow cytometry, ELISA, and CFSE Tregs suppressor assays using CXCR5 &FoxP3-Delta-EGFP knockout &FoxP3-GFP knockin, OT-II transgenic mice and the conditional knockouts for FoxP3-DTR &CD11c-DTR. Investigation of the etiology of host tissue inflammation will also advance the prevention of immune-mediated pathology following other infections, transplantation rejection and autoimmune reactions. Understanding the role of Tregs in UGT inflammation is essential for developing novel immunomodulatory therapeutics for chlamydial infection and other STI's. The PI, Dr. Kathleen A. Kelly is uniquely experienced to investigate murine UGT inflammation following Chlamydia infection and has assembled a team which will enable her to make significant contributions.
Benefits for Public Health Chlamydia trachomatis, an obligate intracellular bacterium, causes the most cases of bacterial sexually transmitted infections (STIs) in the US and can result in about one million cases of immune- mediated pelvic inflammatory disease (PID) and/or infertility in infected females annually. Treating PID and infertility burdens the US health care system by billions of dollars annually and this proposal examines a potential means (FoxP3+ T regulatory cells) of reducing the number of individuals which develop immune-mediated sequelae following Chlamydia STIs.
|Jiang, Janina; Champion, Cheryl I; Wei, Bo et al. (2013) CD8âºCXCR5âº T cells regulate pathology in the genital tract. Infect Dis Obstet Gynecol 2013:813238|
|Kar, Upendra K; Jiang, Janina; Champion, Cheryl I et al. (2012) Vault nanocapsules as adjuvants favor cell-mediated over antibody-mediated immune responses following immunization of mice. PLoS One 7:e38553|
|Jiang, Janina; Kelly, Kathleen A (2012) Isolation of lymphocytes from mouse genital tract mucosa. J Vis Exp :e4391|
|Jiang, Janina; Kelly, Kathleen A (2011) Phenotype and function of regulatory T cells in the genital tract. Curr Trends Immunol 12:89-94|
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|Liu, Wei; Kelly, Kathleen Ann (2008) Prostaglandin E2 modulates dendritic cell function during chlamydial genital infection. Immunology 123:290-303|
|Kelly, Kathleen A; Butch, Anthony W (2007) Antigen-specific immunoglobulin E+ B cells are preferentially localized within germinal centres. Immunology 120:345-53|
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|Kelly, K A; Rank, R G (1997) Identification of homing receptors that mediate the recruitment of CD4 T cells to the genital tract following intravaginal infection with Chlamydia trachomatis. Infect Immun 65:5198-208|
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