CD4 + CD25 + T Regulatory Cells Inhibit CD8 + IFN-γ Production During Acute and Chronic FIV Infection Utilizing a Membrane TGF-β-Dependent Mechanism

Abstract

CD8⁺ lymphocytes are critical to the control and elimination of viral pathogens. Impaired CD8⁺ responses are well recognized in lentiviral infections; however, the mechanisms underlying CD8⁺ impairment remain elusive. Using the feline immunodeficiency virus (FIV) model for human AIDS, we reported previously that CD4⁺CD25⁺ Treg cells in both the acute and long-term, asymptomatic phase of infection are constitutively activated and suppress CD4⁺CD25^– T cell responses. In the current study, we have demonstrated that CD4⁺CD25⁺ Treg cells suppress CD8⁺ responses to immune stimulation during both the acute and chronic, asymptomatic phase of FIV infection and that the mechanism of suppression may be mediated by membrane-associated TGF-β (mTGF-β) on CD4⁺CD25⁺ lymphocytes. Depletion of CD4⁺CD25⁺ lymphocytes from lymph node suspensions significantly enhanced production of IFN-γ during the acute phase of infection and coculture of CD8⁺ lymphocytes with CD4⁺CD25⁺ lymphocytes resulted in suppression of CD8⁺ IFN-γ during both the acute and chronic stages of infection. FACS analysis indicated that there was TGF-βRII upregulation on CD8⁺ cells from FIV⁺ cats during the acute and chronic stage of infection. In addition, there was upregulation of mTGF-β on the CD4⁺CD25⁺ subset in chronically infected cats. In support of activation of the TGF-β signaling pathway, Western blotting showed Smad 2 phosphorylation in CD8⁺ targets following CD4⁺CD25⁺/CD8⁺ coculture. These results demonstrate the suppressive effect CD4⁺CD25⁺ Treg cells have on the CD8⁺ immune response during the acute and chronic stages of FIV infection and suggest that the mechanism of suppression may be mediated by mTGF-β.