T regulatory Cell Suppression of CD8+ Lymphocyte Responses During FIV Infection.
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2009-01-07
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FOGLE, JONATHAN EDWARD. T regulatory Cell Suppression of CD8+ Lymphocyte Responses During FIV Infection. (under the direction of Mary Tompkins.)
The action of activated CD8+ lymphocytes is critical to the control and elimination of viral pathogens. Impaired CD8+ immune responses are well recognized in lentiviral infections; however, the mechanisms underlying CD8+ impairment are incompletely understood. Using the FIV model for human AIDS, we reported previously that CD4+CD25+ Treg cells in both the acute phase and long-term, asymptomatic phase of infection are constitutively activated and suppress CD4+CD25- T cell immune responses. Building upon these observations, we tested the hypothesis that CD4+CD25+ Treg cells suppress CD8+ responses to immune stimulation during both the acute and chronic, asymptomatic stages of FIV infection. SPF cats were infected with NCSU1 FIV. During the acute stage of infection, plasma viremia as well as PBMC and LN lymphocyte phenotype was assessed at regular intervals. Unfractionated lymph node, CD4+CD25+ depleted lymph node, and CD8+ / CD4+CD25+ co-cultures were assayed for IFNï § production via a feline specific ELISpot. During the chronic, asymptomatic phase of infection, IFNï § mRNA in CD8+ lymphocytes was assessed using real time RT-PCR following CD8+ co-culture with CD4+CD25+ lymphocytes. Our results demonstrated that the CD8+ nadir at 14 days corresponds to peak plasma viremia and is followed by an increase in CD8+ number to greater than pre-infection values. Ex-vivo depletion of CD4+CD25+ lymphocytes from lymph node suspensions significantly enhanced the production of IFNï § during the acute phase of infection. Furthermore, co-culture of CD8+ lymphocytes with CD4+CD25+ lymphocytes results in suppression of CD8+ IFNï § production during both the acute and chronic stages of infection. The same observations were not evident in uninfected cats evaluated in an identical manner. These results demonstrate the profound suppressive effect of CD4+CD25+ T regulatory cells on the CD8+ immune response during the acute and chronic stages of FIV infection.
Although the mechanism of CD4+CD25+ T cell-mediated suppression is controversial, there is strong evidence to suggest that, at least in some models, it occurs via a TGFb / TGFbRII signaling pathway. We hypothesize that during the early acute stage of FIV lentiviral infection, TGFï ¢ is up-regulated on the plasma membrane of Treg cells (mTGFï ¢), which engages TGFï ¢RII on the surface of antigen activated CD8+ cells thus transducing a signal through the Smad pathway for G1 cell cycle arrest (anergy) and effectively aborting CD8+ T cell expansion and a sustained CD8+ immune response. The experiments that follow demonstrate up-regulation of mTGFï ¢ in the CD4+CD25+ subset and up-regulation of TGFï ¢RII in the CD8+ subset of FIV+ cats as assessed by FACS analysis. Furthermore, we demonstrate Smad 2 phosphorylation in CD8+ targets following CD4+CD25+ / CD8+ co-culture.
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T regulatory cell, FIV, CD8+ lymphocyte, AIDS
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Degree
PhD
Discipline
Immunology
