We have demonstrated IL-2 + anti-CD3 Ab stimulated CTL activity exists throughout the human female reproductive tract (RT). T cells from secretory phase uterine endometrium, however, lack lytic function despite the presence of substantial numbers of CD3+CD8+ T cells. High circulating levels of estradiol (E2) and progesterone (P) are present during the secretory phase, when embryo implantation many occur. Low levels of E2/P, present post-menopausally, correlated with the highest levels of endometrial CTL activity. Thus, CTL activity was found to correlate inversely with E2/P hormones within the endometrium, possibly to avoid rejection of the semi-allogeneic embryo. High CTL activities were consistently found in the cervix and vagina, suggesting maximal immunologic protection is provided at these sites. Our overall hypothesis is that CD3+CD8+ T cell lytic function within the female RT is regulated by sex steroid hormones and that this regulation of T cells allows for reproduction while maximizing immune protection. The primary goals of this proposal are to define the mechanisms by which RT CTL lytic function is regulated and to define the involvement of other immune cells, such as T helper cells, macrophages, and NK cells in these pathways. To address these goals we will: 1) define the cell-to-cell interactions that are responsible for the low/no versus high CTL activity phenotypes. An assessment of T cell activation state, proliferative ability, and susceptibility to apoptosis will be included as well. 2) identify how cytokines modulate RT T cell function. Both the production of cytokines and regulation of function by cytokines in vitro will be assessed. 3) evaluate the effect of sex steroid hormones and other steroids on RT T cell function. The effects of endogenous E2/P on T cell cytolytic activity will continue to be analyzed, Modulation of cytokine production, proliferation and differentiation of RT lymphocytes by exogenous E2/P will also be evaluated. The implications of this research are relevant for fertility/infertility, protection against STD, menopausal health concerns, cancer, and other female RT disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI034478-05A1
Application #
6268098
Study Section
Project Start
1998-09-30
Project End
1999-02-28
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Type
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Haddad, Severina N; Wira, Charles R (2014) Estradiol regulation of constitutive and keratinocyte growth factor-induced CCL20 and CXCL1 secretion by mouse uterine epithelial cells. Am J Reprod Immunol 72:34-44
Fahey, John V; Rossoll, Richard M; Wira, Charles R (2005) Sex hormone regulation of anti-bacterial activity in rat uterine secretions and apical release of anti-bacterial factor(s) by uterine epithelial cells in culture. J Steroid Biochem Mol Biol 93:59-66
Wira, Charles R; Rossoll, Richard M; Young, Roger C (2005) Polarized uterine epithelial cells preferentially present antigen at the basolateral surface: role of stromal cells in regulating class II-mediated epithelial cell antigen presentation. J Immunol 175:1795-804
Asin, Susana N; Fanger, Michael W; Wildt-Perinic, Dunja et al. (2004) Transmission of HIV-1 by primary human uterine epithelial cells and stromal fibroblasts. J Infect Dis 190:236-45
Yeaman, Grant R; Asin, Susana; Weldon, Sally et al. (2004) Chemokine receptor expression in the human ectocervix: implications for infection by the human immunodeficiency virus-type I. Immunology 113:524-33
Yeaman, Grant R; Howell, Alexandra L; Weldon, Sally et al. (2003) Human immunodeficiency virus receptor and coreceptor expression on human uterine epithelial cells: regulation of expression during the menstrual cycle and implications for human immunodeficiency virus infection. Immunology 109:137-46
Wira, Charles R; Fahey, John V; Abrahams, Vikki M et al. (2003) Influence of stage of the reproductive cycle and estradiol on thymus cell antigen presentation. J Steroid Biochem Mol Biol 84:79-87
Wira, Charles R; Rossoll, Richard M (2003) Oestradiol regulation of antigen presentation by uterine stromal cells: role of transforming growth factor-beta production by epithelial cells in mediating antigen-presenting cell function. Immunology 109:398-406
Abrahams, Vikki M; Collins, Jane E; Wira, Charles R et al. (2003) Inhibition of human polymorphonuclear cell oxidative burst by 17-beta-estradiol and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Am J Reprod Immunol 50:463-72
Wira, Charles R; Roche, Marcie A; Rossoll, Richard M (2002) Antigen presentation by vaginal cells: role of TGFbeta as a mediator of estradiol inhibition of antigen presentation. Endocrinology 143:2872-9

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