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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0900350v1 183/3/1636    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Myers, L. Articles by Hasenkrug, K. J. PubMed PubMed Citation Articles by Myers, L. Articles by Hasenkrug, K. J.

Tissue-Specific Abundance of Regulatory T Cells Correlates with CD8⁺ T Cell Dysfunction and Chronic Retrovirus Loads¹

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840

Infection of mice with Friend virus induces the activation of CD4⁺ regulatory T cells (Tregs) that suppress virus-specific CD8⁺ T cells. This suppression leads to incomplete virus clearance and the establishment of virus persistence. We now show that Treg-mediated suppression of CD8⁺ T cells is tissue specific, occurring in the spleen but not the liver. Regardless of infection status, there was a 5-fold lower proportion of Tregs in the liver than in the spleen, much lower absolute cell numbers, and the relatively few Tregs present expressed less CD25. Results indicated that reduced expression of CD25 on liver Tregs was due to microenvironmental factors including low levels of IL-2 production by CD4⁺ Th cells in that tissue. Low CD25 expression on liver Tregs did not impair their ability to suppress CD8⁺ T cells in vitro. Correlating with the decreased proportion of Tregs in the liver was a significantly increased proportion of virus-specific CD8⁺ T cells compared with the spleen. The virus-specific CD8⁺ T cells from the liver did not appear suppressed given that they produced both IFN- and granzyme B, and they also showed evidence of recent cytolytic activity (CD107a⁺). The functional phenotype of the virus-specific CD8⁺ T cells correlated with a 10-fold reduction of chronic Friend virus levels in the liver compared with the spleen. Thus, suppression of CD8⁺ T cells by virus-induced Tregs occurs in a tissue-specific manner and correlates with profound effects on localized levels of chronic infection.

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 research was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Kim J. Hasenkrug, Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840. E-mail address: khasenkrug{at}nih.gov

³ Abbreviations used in this paper: FV, Friend virus; Treg, regulatory T cell; F-MuLV, Friend murine leukemia helper virus; CD62L, L-selectin.

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