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Chemokine and Cytokine Mediated Loss of Regulatory T Cells in Lymph Nodes during Pathogenic Simian Immunodeficiency Virus Infection¹

Shulin Qin^2,*, Yongjun Sui^2,*, Adam C. Soloff^*,, Beth A. Fallert Junecko^*, Denise E. Kirschner^||, Michael A. Murphey-Corb, Simon C. Watkins, Patrick M. Tarwater^#, James E. Pease^**, Simon M. Barratt-Boyes^*,,¶ and Todd A. Reinhart^3,*

^* Department of Infectious Diseases and Microbiology, Graduate School of Public Health, Center for Vaccine Research, Department of Molecular Genetics and Biochemistry, Department of Cell Biology and Physiology, and ^¶ Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260; ^|| Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109; ^# Departments of Biostatistics and Epidemiology, University of Texas Health Science Center, Houston, TX 77030; and ^** Leukocyte Biology Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom

Regulatory T cells (T_reg) play key roles in immune regulation through multiple modes of suppression. The effects of HIV-1 infection on T_reg levels in lymphoid tissues remain incompletely understood. To explore this issue, we have measured the levels of forkhead box protein 3 (FOXP3)-positive cells and associated immunomodulatory genes in a pathogenic simian immunodeficiency virus/macaque model and found that a loss of T_reg in lymph nodes occurred following simian immunodeficiency virus infection. Changes in expression of the ligands for CXCR3, CCR4, and CCR7 and the cytokines TGF-β and IL-2 were all linked to this loss of T_reg, which in turn was linked with increased levels of cellular activation. Our findings identify three mechanisms that likely contribute to SIV-driven loss of T_reg, including reduced levels of cytokines associated with T_reg differentiation and altered expression of agonist and antagonist chemokines. The loss of T_reg and the associated cellular activation in lymphoid tissues is consistent with the events in HIV-1-infected individuals and suggest that components of the T_reg differentiation and trafficking network could be targets for therapeutic intervention.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Public Health Service Grants AI060422 (to T.A.R.), HL072682 (to D.E.K.), and U54 RR02241 (to S.C.W.).

² S.Q. and Y.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Todd A. Reinhart, Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, 606 Parran Hall, 130 DeSoto Street, Pittsburgh, PA 15261. E-mail address: reinhar{at}pitt.edu

⁴ Abbreviations used in this paper: T_reg, regulatory T cell; LN, lymph node; SIV, simian immunodeficiency virus; PI, postinfection; FOXP3, forkhead box protein P3.

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The JI 2008 180: 5155-5156. [Full Text]