In addition to regulating autoimmunity and antitumor immunity, CD4؉ CD25 Natural regulatory T (Treg) cells are among a growing family of T-cell subsets found to have a negative regulatory effect on immune responses (1,24,(31)(32)(33)36). These cells represent 5 to 10% of all CD4 ϩ T cells in the mouse and are characterized by the expression of FoxP3, a transcription factor determining regulatory cell lineage development (14). Most Treg cells also express the high-affinity interleukin-2 (IL-2) receptor CD25, and IL-2 has been shown to be critical for Treg-cell maintenance and function (41). CD8 ϩ T-cell effector functions and proliferation are often dampened by negative regulation by Treg cells (31, 32). Anti-CD25 antibody depletion studies in the mouse show increased CD8 ϩ T-cell responses following depletion of Treg cells and often increased clearance of the pathogen (8,9,12,29,39,40 [187][188][189][190][191][192][193][194][195] ) responses can be studied simultaneously (19,34,35). This model allows us to look at the relative contribution of epitope-specific CD8 Given the suppressive potential of Treg cells during viral infections, we hypothesized that depletion of Treg cells prior to intranasal infection with RSV would facilitate viral clearance from the lungs yet increase illness due to CD8 ϩ -mediated immunopathology. Surprisingly, we found that animals that were Treg cell depleted experienced less efficient RSV clearance and a delay in CD8 ϩ T-cell responses in the lung despite increased levels of RSV-specific CD8 ϩ T cells in the lungdraining lymph node and spleen early after infection. However, increased cytokine and chemokine expression 7 days postinfection and exaggerated CD8 ϩ T-cell responses in the lung after the first week of infection resulted in a later exacerbation of disease and slower recovery from illness. Treg-cell depletion not only altered the kinetics of the CD8 ϩ T-cell response but also resulted in systemic modulation of the immunodominance disparity between the K d M2 82-90 and the D b M 187-195 epitopes. MATERIALS AND METHODSMice. Adult (6-to 10-week-old) female CB6F1 mice (Jackson Laboratories, Bar Harbor, ME) were used for all experiments. All mice were housed in our animal care facility at the National Institute of Allergy and Infections Diseases under specific-pathogen-free conditions and maintained on standard rodent

We have previously shown that the SH2 domain-containing protein tyrosine phosphatase SHP-1 plays a critical role in controlling virus infection in CNS glia in vivo and in vitro. The present study addressed whether increased virus replication in SHP-1-deficient glia in vitro may be a result of altered expression of inducible nitric oxide synthase (iNOS/NOS2). First, we observed a profound reduction in iNOS protein expression and production of nitric oxide (NO) in response to the viral mimic double-stranded RNA (dsRNA), despite the induction of high levels of iNOS mRNA, in SHP-1-deficient motheaten mouse compared to wild type littermate mouse glia. Because both iNOS expression and NO production are suppressed by multiple pathways involving arginase I activity, it was important that we observed abnormally high constitutive expression of arginase I in cultured glia of SHP-1-deficient compared to wild type mice. Further, both constitutive and IL-4/IL-10-induced expression of arginase I correlated with elevated STAT6 nuclear binding activity, decreased NO production, and increased virus replication in motheaten compared to wild type astrocytes. These findings provide the first evidence of an inverse relationship between NO and arginase I activity regulated by SHP-1 in CNS glia that is relevant to modulation of innate anti-viral responses. Thus, we propose that SHP-1 is a critical regulator of innate immunity to virus infections in CNS cells.

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