Abstract
Murine genital infection induced with the mouse pneumonitis biovar of Chlamydia trachomatis (MoPn) elicits a short-lived protective immunity mediated primarily by Th1 CD4 cells. To understand the development of local cell-mediated immunity against C. trachomatis infection, we investigated the mechanism(s) which mediates CD4 lymphocyte migration to the genital mucosa by identifying molecules that could support this process. We found that primarily CD4 cells were recruited to the genital tract (GT) during primary and challenge MoPn infection. Peak levels were found 21 days after primary inoculation (15.4% +/- 2.7%) and 7 days (31.3% +/- 8.5%) after challenge but diminished after resolution of infection. The CD4 cells appeared to be recruited to the GT in response to infection since these cells expressed the profile of activated, or memory, cells. We also observed up-regulation of homing receptors containing LFA-1 (CD11a) and alpha4 (CD49d) on GT CD4 cells over the course of infection. Furthermore, the mucosal homing receptor chain, beta7, but not the peripheral homing receptor chain beta1 (CD29), was detected on GT CD4 cells. MoPn-infected GT tissue expressed the endothelial cell ligands vascular cell adhesion molecule 1 (VCAM-1), intracellular adhesion molecule 1 (ICAM-1), and mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), which correspond to the homing receptors on GT CD4 cells. Interestingly, VCAM-1 and MAdCAM-1 were not expressed in the GTs of uninfected mice but were temporarily induced following infection, indicating that expression of endothelial ligands in the GT are regulated by chlamydial infection. These data suggest that recruitment of CD4 cells to the GT is mediated through LFA-1:ICAM-1 and alpha4beta7:MAdCAM-1-VCAM-1 interactions.
Full Text
The Full Text of this article is available as a PDF (1.3 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Andrew D. P., Berlin C., Honda S., Yoshino T., Hamann A., Holzmann B., Kilshaw P. J., Butcher E. C. Distinct but overlapping epitopes are involved in alpha 4 beta 7-mediated adhesion to vascular cell adhesion molecule-1, mucosal addressin-1, fibronectin, and lymphocyte aggregation. J Immunol. 1994 Nov 1;153(9):3847–3861. [PubMed] [Google Scholar]
- Berlin C., Berg E. L., Briskin M. J., Andrew D. P., Kilshaw P. J., Holzmann B., Weissman I. L., Hamann A., Butcher E. C. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell. 1993 Jul 16;74(1):185–195. doi: 10.1016/0092-8674(93)90305-a. [DOI] [PubMed] [Google Scholar]
- Beutler A. M., Whittum-Hudson J. A., Nanagara R., Schumacher H. R., Hudson A. P. Intracellular location of inapparently infecting Chlamydia in synovial tissue from patients with Reiter's syndrome. Immunol Res. 1994;13(2-3):163–171. doi: 10.1007/BF02918277. [DOI] [PubMed] [Google Scholar]
- Bevilacqua M. P. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol. 1993;11:767–804. doi: 10.1146/annurev.iy.11.040193.004003. [DOI] [PubMed] [Google Scholar]
- Budd R. C., Cerottini J. C., Horvath C., Bron C., Pedrazzini T., Howe R. C., MacDonald H. R. Distinction of virgin and memory T lymphocytes. Stable acquisition of the Pgp-1 glycoprotein concomitant with antigenic stimulation. J Immunol. 1987 May 15;138(10):3120–3129. [PubMed] [Google Scholar]
- Cain T. K., Rank R. G. Local Th1-like responses are induced by intravaginal infection of mice with the mouse pneumonitis biovar of Chlamydia trachomatis. Infect Immun. 1995 May;63(5):1784–1789. doi: 10.1128/iai.63.5.1784-1789.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carlos T. M., Harlan J. M. Leukocyte-endothelial adhesion molecules. Blood. 1994 Oct 1;84(7):2068–2101. [PubMed] [Google Scholar]
- Cates W., Jr, Wasserheit J. N. Genital chlamydial infections: epidemiology and reproductive sequelae. Am J Obstet Gynecol. 1991 Jun;164(6 Pt 2):1771–1781. doi: 10.1016/0002-9378(91)90559-a. [DOI] [PubMed] [Google Scholar]
- Cotter T. W., Meng Q., Shen Z. L., Zhang Y. X., Su H., Caldwell H. D. Protective efficacy of major outer membrane protein-specific immunoglobulin A (IgA) and IgG monoclonal antibodies in a murine model of Chlamydia trachomatis genital tract infection. Infect Immun. 1995 Dec;63(12):4704–4714. doi: 10.1128/iai.63.12.4704-4714.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coulson P. S., Wilson R. A. Recruitment of lymphocytes to the lung through vaccination enhances the immunity of mice exposed to irradiated schistosomes. Infect Immun. 1997 Jan;65(1):42–48. doi: 10.1128/iai.65.1.42-48.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Darville T., Andrews C. W., Jr, Laffoon K. K., Shymasani W., Kishen L. R., Rank R. G. Mouse strain-dependent variation in the course and outcome of chlamydial genital tract infection is associated with differences in host response. Infect Immun. 1997 Aug;65(8):3065–3073. doi: 10.1128/iai.65.8.3065-3073.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dedera D. A., Urashima M., Chauhan D., LeBrun D. P., Bronson R. T., Anderson K. C. Interleukin-6 is required for pristane-induced plasma cell hyperplasia in mice. Br J Haematol. 1996 Jul;94(1):53–61. doi: 10.1046/j.1365-2141.1996.6282074.x. [DOI] [PubMed] [Google Scholar]
- Dustin M. L., Springer T. A. Lymphocyte function-associated antigen-1 (LFA-1) interaction with intercellular adhesion molecule-1 (ICAM-1) is one of at least three mechanisms for lymphocyte adhesion to cultured endothelial cells. J Cell Biol. 1988 Jul;107(1):321–331. doi: 10.1083/jcb.107.1.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fidel P. L., Jr, Wolf N. A., KuKuruga M. A. T lymphocytes in the murine vaginal mucosa are phenotypically distinct from those in the periphery. Infect Immun. 1996 Sep;64(9):3793–3799. doi: 10.1128/iai.64.9.3793-3799.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Figdor C. G., van Kooyk Y., Keizer G. D. On the mode of action of LFA-1. Immunol Today. 1990 Aug;11(8):277–280. doi: 10.1016/0167-5699(90)90112-m. [DOI] [PubMed] [Google Scholar]
- Ford W. L., Gowans J. L. The traffic of lymphocytes. Semin Hematol. 1969 Jan;6(1):67–83. [PubMed] [Google Scholar]
- Fuller K. A., Kanagawa O., Nahm M. H. T cells within germinal centers are specific for the immunizing antigen. J Immunol. 1993 Nov 1;151(9):4505–4512. [PubMed] [Google Scholar]
- Galdiero M., de l'Ero G. C., Marcatili A. Cytokine and adhesion molecule expression in human monocytes and endothelial cells stimulated with bacterial heat shock proteins. Infect Immun. 1997 Feb;65(2):699–707. doi: 10.1128/iai.65.2.699-707.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Girard J. P., Springer T. A. High endothelial venules (HEVs): specialized endothelium for lymphocyte migration. Immunol Today. 1995 Sep;16(9):449–457. doi: 10.1016/0167-5699(95)80023-9. [DOI] [PubMed] [Google Scholar]
- Hamann A., Jablonski-Westrich D., Scholz K. U., Duijvestijn A., Butcher E. C., Thiele H. G. Regulation of lymphocyte homing. I. Alterations in homing receptor expression and organ-specific high endothelial venule binding of lymphocytes upon activation. J Immunol. 1988 Feb 1;140(3):737–743. [PubMed] [Google Scholar]
- Igietseme J. U., Magee D. M., Williams D. M., Rank R. G. Role for CD8+ T cells in antichlamydial immunity defined by Chlamydia-specific T-lymphocyte clones. Infect Immun. 1994 Nov;62(11):5195–5197. doi: 10.1128/iai.62.11.5195-5197.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Igietseme J. U., Ramsey K. H., Magee D. M., Williams D. M., Kincy T. J., Rank R. G. Resolution of murine chlamydial genital infection by the adoptive transfer of a biovar-specific, Th1 lymphocyte clone. Reg Immunol. 1993 Nov-Dec;5(6):317–324. [PubMed] [Google Scholar]
- Igietseme J. U., Rank R. G. Susceptibility to reinfection after a primary chlamydial genital infection is associated with a decrease of antigen-specific T cells in the genital tract. Infect Immun. 1991 Apr;59(4):1346–1351. doi: 10.1128/iai.59.4.1346-1351.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ingalls R. R., Rice P. A., Qureshi N., Takayama K., Lin J. S., Golenbock D. T. The inflammatory cytokine response to Chlamydia trachomatis infection is endotoxin mediated. Infect Immun. 1995 Aug;63(8):3125–3130. doi: 10.1128/iai.63.8.3125-3130.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Issekutz T. B. Inhibition of in vivo lymphocyte migration to inflammation and homing to lymphoid tissues by the TA-2 monoclonal antibody. A likely role for VLA-4 in vivo. J Immunol. 1991 Dec 15;147(12):4178–4184. [PubMed] [Google Scholar]
- Kantele A., Kantele J. M., Savilahti E., Westerholm M., Arvilommi H., Lazarovits A., Butcher E. C., Mäkelä P. H. Homing potentials of circulating lymphocytes in humans depend on the site of activation: oral, but not parenteral, typhoid vaccination induces circulating antibody-secreting cells that all bear homing receptors directing them to the gut. J Immunol. 1997 Jan 15;158(2):574–579. [PubMed] [Google Scholar]
- Katz B. P., Batteiger B. E., Jones R. B. Effect of prior sexually transmitted disease on the isolation of Chlamydia trachomatis. Sex Transm Dis. 1987 Jul-Sep;14(3):160–164. doi: 10.1097/00007435-198707000-00008. [DOI] [PubMed] [Google Scholar]
- Kelly K. A., Bucy R. P., Nahm M. H. Germinal center T cells exhibit properties of memory helper T cells. Cell Immunol. 1995 Jul;163(2):206–214. doi: 10.1006/cimm.1995.1118. [DOI] [PubMed] [Google Scholar]
- Kelly K. A., Robinson E. A., Rank R. G. Initial route of antigen administration alters the T-cell cytokine profile produced in response to the mouse pneumonitis biovar of Chlamydia trachomatis following genital infection. Infect Immun. 1996 Dec;64(12):4976–4983. doi: 10.1128/iai.64.12.4976-4983.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lenter M., Uhlig H., Hamann A., Jenö P., Imhof B., Vestweber D. A monoclonal antibody against an activation epitope on mouse integrin chain beta 1 blocks adhesion of lymphocytes to the endothelial integrin alpha 6 beta 1. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9051–9055. doi: 10.1073/pnas.90.19.9051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lloyd A. R., Oppenheim J. J., Kelvin D. J., Taub D. D. Chemokines regulate T cell adherence to recombinant adhesion molecules and extracellular matrix proteins. J Immunol. 1996 Feb 1;156(3):932–938. [PubMed] [Google Scholar]
- Lobb R. R., Hemler M. E. The pathophysiologic role of alpha 4 integrins in vivo. J Clin Invest. 1994 Nov;94(5):1722–1728. doi: 10.1172/JCI117519. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mackay C. R. Migration pathways and immunologic memory among T lymphocytes. Semin Immunol. 1992 Feb;4(1):51–58. [PubMed] [Google Scholar]
- Mackay C. R. T-cell memory: the connection between function, phenotype and migration pathways. Immunol Today. 1991 Jun;12(6):189–192. doi: 10.1016/0167-5699(91)90051-T. [DOI] [PubMed] [Google Scholar]
- Magee D. M., Smith J. G., Bleicker C. A., Carter C. J., Bonewald L. F., Schachter J., Williams D. M. Chlamydia trachomatis pneumonia induces in vivo production of interleukin-1 and -6. Infect Immun. 1992 Mar;60(3):1217–1220. doi: 10.1128/iai.60.3.1217-1220.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Magee D. M., Williams D. M., Smith J. G., Bleicker C. A., Grubbs B. G., Schachter J., Rank R. G. Role of CD8 T cells in primary Chlamydia infection. Infect Immun. 1995 Feb;63(2):516–521. doi: 10.1128/iai.63.2.516-521.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McDermott M. R., Bienenstock J. Evidence for a common mucosal immunologic system. I. Migration of B immunoblasts into intestinal, respiratory, and genital tissues. J Immunol. 1979 May;122(5):1892–1898. [PubMed] [Google Scholar]
- Morrison R. P., Feilzer K., Tumas D. B. Gene knockout mice establish a primary protective role for major histocompatibility complex class II-restricted responses in Chlamydia trachomatis genital tract infection. Infect Immun. 1995 Dec;63(12):4661–4668. doi: 10.1128/iai.63.12.4661-4668.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Osborn L. Leukocyte adhesion to endothelium in inflammation. Cell. 1990 Jul 13;62(1):3–6. doi: 10.1016/0092-8674(90)90230-c. [DOI] [PubMed] [Google Scholar]
- Parr M. B., Parr E. L. Langerhans cells and T lymphocyte subsets in the murine vagina and cervix. Biol Reprod. 1991 Mar;44(3):491–498. doi: 10.1095/biolreprod44.3.491. [DOI] [PubMed] [Google Scholar]
- Perry L. L., Feilzer K., Caldwell H. D. Immunity to Chlamydia trachomatis is mediated by T helper 1 cells through IFN-gamma-dependent and -independent pathways. J Immunol. 1997 Apr 1;158(7):3344–3352. [PubMed] [Google Scholar]
- Picker L. J. Control of lymphocyte homing. Curr Opin Immunol. 1994 Jun;6(3):394–406. doi: 10.1016/0952-7915(94)90118-x. [DOI] [PubMed] [Google Scholar]
- Ramsey K. H., Newhall W. J., 5th, Rank R. G. Humoral immune response to chlamydial genital infection of mice with the agent of mouse pneumonitis. Infect Immun. 1989 Aug;57(8):2441–2446. doi: 10.1128/iai.57.8.2441-2446.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ramsey K. H., Rank R. G. Resolution of chlamydial genital infection with antigen-specific T-lymphocyte lines. Infect Immun. 1991 Mar;59(3):925–931. doi: 10.1128/iai.59.3.925-931.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ramsey K. H., Soderberg L. S., Rank R. G. Resolution of chlamydial genital infection in B-cell-deficient mice and immunity to reinfection. Infect Immun. 1988 May;56(5):1320–1325. doi: 10.1128/iai.56.5.1320-1325.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rank R. G., Barron A. L. Humoral immune response in acquired immunity to chlamydial genital infection of female guinea pigs. Infect Immun. 1983 Jan;39(1):463–465. doi: 10.1128/iai.39.1.463-465.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rank R. G., Batteiger B. E., Soderberg L. S. Susceptibility to reinfection after a primary chlamydial genital infection. Infect Immun. 1988 Sep;56(9):2243–2249. doi: 10.1128/iai.56.9.2243-2249.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rank R. G., Sanders M. M., Kidd A. T. Influence of the estrous cycle on the development of upper genital tract pathology as a result of chlamydial infection in the guinea pig model of pelvic inflammatory disease. Am J Pathol. 1993 Apr;142(4):1291–1296. [PMC free article] [PubMed] [Google Scholar]
- Rank R. G., White H. J., Barron A. L. Humoral immunity in the resolution of genital infection in female guinea pigs infected with the agent of guinea pig inclusion conjunctivitis. Infect Immun. 1979 Nov;26(2):573–579. doi: 10.1128/iai.26.2.573-579.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rice G. E., Munro J. M., Bevilacqua M. P. Inducible cell adhesion molecule 110 (INCAM-110) is an endothelial receptor for lymphocytes. A CD11/CD18-independent adhesion mechanism. J Exp Med. 1990 Apr 1;171(4):1369–1374. doi: 10.1084/jem.171.4.1369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rott L. S., Briskin M. J., Andrew D. P., Berg E. L., Butcher E. C. A fundamental subdivision of circulating lymphocytes defined by adhesion to mucosal addressin cell adhesion molecule-1. Comparison with vascular cell adhesion molecule-1 and correlation with beta 7 integrins and memory differentiation. J Immunol. 1996 May 15;156(10):3727–3736. [PubMed] [Google Scholar]
- Schachter J. Chlamydial infections (third of three parts). N Engl J Med. 1978 Mar 9;298(10):540–549. doi: 10.1056/NEJM197803092981005. [DOI] [PubMed] [Google Scholar]
- Schachter J., Cles L. D., Ray R. M., Hesse F. E. Is there immunity to chlamydial infections of the human genital tract? Sex Transm Dis. 1983 Jul-Sep;10(3):123–125. doi: 10.1097/00007435-198307000-00004. [DOI] [PubMed] [Google Scholar]
- Shimizu Y., van Seventer G. A., Horgan K. J., Shaw S. Roles of adhesion molecules in T-cell recognition: fundamental similarities between four integrins on resting human T cells (LFA-1, VLA-4, VLA-5, VLA-6) in expression, binding, and costimulation. Immunol Rev. 1990 Apr;114:109–143. doi: 10.1111/j.1600-065x.1990.tb00563.x. [DOI] [PubMed] [Google Scholar]
- Springer T. A. Adhesion receptors of the immune system. Nature. 1990 Aug 2;346(6283):425–434. doi: 10.1038/346425a0. [DOI] [PubMed] [Google Scholar]
- Starnbach M. N., Bevan M. J., Lampe M. F. Protective cytotoxic T lymphocytes are induced during murine infection with Chlamydia trachomatis. J Immunol. 1994 Dec 1;153(11):5183–5189. [PubMed] [Google Scholar]
- Streeter P. R., Berg E. L., Rouse B. T., Bargatze R. F., Butcher E. C. A tissue-specific endothelial cell molecule involved in lymphocyte homing. Nature. 1988 Jan 7;331(6151):41–46. doi: 10.1038/331041a0. [DOI] [PubMed] [Google Scholar]
- Streeter P. R., Rouse B. T., Butcher E. C. Immunohistologic and functional characterization of a vascular addressin involved in lymphocyte homing into peripheral lymph nodes. J Cell Biol. 1988 Nov;107(5):1853–1862. doi: 10.1083/jcb.107.5.1853. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Su H., Caldwell H. D. CD4+ T cells play a significant role in adoptive immunity to Chlamydia trachomatis infection of the mouse genital tract. Infect Immun. 1995 Sep;63(9):3302–3308. doi: 10.1128/iai.63.9.3302-3308.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Su H., Feilzer K., Caldwell H. D., Morrison R. P. Chlamydia trachomatis genital tract infection of antibody-deficient gene knockout mice. Infect Immun. 1997 Jun;65(6):1993–1999. doi: 10.1128/iai.65.6.1993-1999.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Williams D. M., Grubbs B. G., Kelly K., Pack E., Rank R. G. Role of gamma-delta T cells in murine Chlamydia trachomatis infection. Infect Immun. 1996 Sep;64(9):3916–3919. doi: 10.1128/iai.64.9.3916-3919.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wølner-Hanssen P., Mårdh P. A., Møller B., Weström L. Endometrial infection in women with Chlamydial salpingitis. Sex Transm Dis. 1982 Apr-Jun;9(2):84–88. doi: 10.1097/00007435-198204000-00006. [DOI] [PubMed] [Google Scholar]
- Yednock T. A., Cannon C., Fritz L. C., Sanchez-Madrid F., Steinman L., Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature. 1992 Mar 5;356(6364):63–66. doi: 10.1038/356063a0. [DOI] [PubMed] [Google Scholar]