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Regulatory T-Cell Markers, Indoleamine 2,3-Dioxygenase, and Virus Levels in Spleen and Gut during Progressive Simian Immunodeficiency Virus Infection

Experimental Immunology Branch, CCR, National Cancer Institute, National Institutes of Health, Bethesda, Maryland,¹ Animal Models and Retroviral Vaccines Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland,² Department of General and Experimental Pathology, Medical University of Bialystok Mickiewicza 2c, 15-222 Bialystok, Poland,³ Division of Biological Chemistry Biocentre, Innsbruck Medical University, Ludwig Boltzmann Institute of AIDS-Research, Innsbruck, Austria,⁴ Center for Infectious Medicine, Division of Infectious Diseases, Karolinska Institute, Karolinska University Hospital, 141 86 Stockholm, Sweden,⁵ Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio⁶

Received 9 April 2007/ Accepted 8 August 2007

High levels of viral replication occur in gut-associated lymphoid tissue (GALT) and other lymphoid tissues (LT) since the early phase of human/simian immunodeficiency virus (HIV/SIV) infection. Regulatory T cells (T_reg), a subset of immunosuppressive T cells expressing CTLA-4 and the FoxP3 transcription factor, accumulate in LT during HIV/SIV infection. Here we show that FoxP3 and CTLA-4 mRNA are increased in leukocytes from the spleens, lymph nodes (LN), and mucosal sites of chronically SIV-infected macaques with high viremia (SIV_HI) compared to animals with low viremia (SIV_LO). FoxP3 and CTLA-4 correlated with SIV RNA levels in tissues; SIV virus levels in the spleen, inguinal LN, mesenteric LN, colon, and jejunum directly correlated with the plasma virus level. Importantly, CTLA-4 and FoxP3 mRNA were predominantly increased in the CD25^– subpopulation of leukocytes from SIV_HI, further challenging the classical definition of T_reg as CD4⁺ CD25⁺ T cells. Similar to CTLA-4 and FoxP3, expression of indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme induced by T_reg in antigen-presenting cells, was increased in the spleens, mesenteric LN, colons, and jejuna from SIV_HI compared to SIV_LO and directly correlated to SIV RNA in the same tissues. Accordingly, plasma kynurenine/tryptophan, a marker for IDO enzymatic activity, was significantly higher in SIV_HI compared to SIV_LO and correlated with plasma viral levels. Increased T_reg and IDO in LT of SIV-infected macaques may be the consequence of increased tissue inflammation and/or may favor virus replication during the chronic phase of SIV infection.

Published ahead of print on 22 August 2007.

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