Toll-like Receptor Ligands Induce Human T Cell Activation and Death, a Model for HIV Pathogenesis

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2008 Apr 3

PMID 18382686

Citations 79

Authors

Nicholas Funderburg

Angel A Luciano

Wei Jiang

Benigno Rodriguez

Scott F Sieg

Michael M Lederman

Affiliations

Soon will be listed here.

Abstract

Background: Recently, heightened systemic translocation of microbial products was found in persons with chronic HIV infection and this was linked to immune activation and CD4(+) T cell homeostasis.

Methodology: We examined here the effects of microbial Toll-like receptor (TLR) ligands on T cell activation in vitro.

Conclusions/findings: We show that exposure to TLR ligands results in activation of memory and effector CD4(+) and CD8(+) T cells. After exposure to each of 8 different ligands that activate TLRs 2, 3, 4, 5, 7, 8, and 9, CD8(+) T cells are activated and gain expression of the C type lectin CD69 that may promote their retention in lymphoid tissues. In contrast, CD4(+) T cells rarely increase CD69 expression but instead enter cell cycle. Despite activation and cell cycle entry, CD4(+) T cells divide poorly and instead, disproportionately undergo activation-induced cell death. Systemic exposure to TLR agonists may therefore increase immune activation, effector cell sequestration in lymphoid tissues and T cell turnover. These events may contribute to the pathogenesis of immune dysfunction and CD4+ T cell losses in chronic infection with the human immunodeficiency virus.

Citing Articles

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References

Brenchley J, Price D, Schacker T, Asher T, Silvestri G, Rao S . Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006; 12(12):1365-71. DOI: 10.1038/nm1511. View

Abrams D, Lewis B, Beckstead J, Casavant C, Drew W . Persistent diffuse lymphadenopathy in homosexual men: endpoint or prodrome?. Ann Intern Med. 1984; 100(6):801-8. DOI: 10.7326/0003-4819-100-6-801. View

Crellin N, Garcia R, Hadisfar O, Allan S, Steiner T, Levings M . Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J Immunol. 2005; 175(12):8051-9. DOI: 10.4049/jimmunol.175.12.8051. View

Sancho D, Gomez M, Sanchez-Madrid F . CD69 is an immunoregulatory molecule induced following activation. Trends Immunol. 2005; 26(3):136-40. DOI: 10.1016/j.it.2004.12.006. View

Andersson J, Fehniger T, Patterson B, Pottage J, Agnoli M, Jones P . Early reduction of immune activation in lymphoid tissue following highly active HIV therapy. AIDS. 1998; 12(11):F123-9. DOI: 10.1097/00002030-199811000-00004. View

Jiang W, Lederman M, Harding C, Rodriguez B, Mohner R, Sieg S . TLR9 stimulation drives naïve B cells to proliferate and to attain enhanced antigen presenting function. Eur J Immunol. 2007; 37(8):2205-13. DOI: 10.1002/eji.200636984. View

Lempicki R, Kovacs J, Baseler M, Adelsberger J, Dewar R, Natarajan V . Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients. Proc Natl Acad Sci U S A. 2000; 97(25):13778-83. PMC: 17652. DOI: 10.1073/pnas.250472097. View

Picker L, Hagen S, Lum R, Reed-Inderbitzin E, Daly L, Sylwester A . Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection. J Exp Med. 2004; 200(10):1299-314. PMC: 2211921. DOI: 10.1084/jem.20041049. View

Tenner-Racz K, Racz P, Thome C, Meyer C, Anderson P, Schlossman S . Cytotoxic effector cell granules recognized by the monoclonal antibody TIA-1 are present in CD8+ lymphocytes in lymph nodes of human immunodeficiency virus-1-infected patients. Am J Pathol. 1993; 142(6):1750-8. PMC: 1886982. View

10.

Zanin-Zhorov A, Tal-Lapidot G, Cahalon L, Cohen-Sfady M, Pevsner-Fischer M, Lider O . Cutting edge: T cells respond to lipopolysaccharide innately via TLR4 signaling. J Immunol. 2007; 179(1):41-4. DOI: 10.4049/jimmunol.179.1.41. View

11.

Beignon A, McKenna K, Skoberne M, Manches O, DaSilva I, Kavanagh D . Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest. 2005; 115(11):3265-75. PMC: 1253628. DOI: 10.1172/JCI26032. View

12.

Cheynier R, Henrichwark S, Hadida F, Pelletier E, Oksenhendler E, Autran B . HIV and T cell expansion in splenic white pulps is accompanied by infiltration of HIV-specific cytotoxic T lymphocytes. Cell. 1994; 78(3):373-87. DOI: 10.1016/0092-8674(94)90417-0. View

13.

Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S . Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004; 303(5663):1526-9. DOI: 10.1126/science.1093620. View

14.

Caron G, Duluc D, Fremaux I, Jeannin P, David C, Gascan H . Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells. J Immunol. 2005; 175(3):1551-7. DOI: 10.4049/jimmunol.175.3.1551. View

15.

Deeks S, Kitchen C, Liu L, Guo H, Gascon R, Narvaez A . Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood. 2004; 104(4):942-7. DOI: 10.1182/blood-2003-09-3333. View

16.

Biancotto A, Grivel J, Iglehart S, Vanpouille C, Lisco A, Sieg S . Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1. Blood. 2007; 109(10):4272-9. PMC: 1885500. DOI: 10.1182/blood-2006-11-055764. View

17.

Wilson C, Ellenberg J, Douglas S, Moscicki A, Holland C . CD8+CD38+ T cells but not HIV type 1 RNA viral load predict CD4+ T cell loss in a predominantly minority female HIV+ adolescent population. AIDS Res Hum Retroviruses. 2004; 20(3):263-9. DOI: 10.1089/088922204322996482. View

18.

Kovacs J, Lempicki R, Sidorov I, Adelsberger J, Herpin B, Metcalf J . Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J Exp Med. 2001; 194(12):1731-41. PMC: 2193579. DOI: 10.1084/jem.194.12.1731. View

19.

Giorgi J, Hultin L, McKeating J, Johnson T, Owens B, Jacobson L . Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis. 1999; 179(4):859-70. DOI: 10.1086/314660. View

20.

Bernasconi N, Traggiai E, Lanzavecchia A . Maintenance of serological memory by polyclonal activation of human memory B cells. Science. 2002; 298(5601):2199-202. DOI: 10.1126/science.1076071. View