T regulatory Cell Suppression of CD8+ Lymphocyte Responses During FIV Infection.

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dc.contributor.advisor Fred Fuller, Committee Member en_US
dc.contributor.advisor Gregg Dean, Committee Member en_US
dc.contributor.advisor Ed Breitschwerdt, Committee Member en_US
dc.contributor.advisor Mary B. Tompkins, Committee Chair en_US
dc.contributor.author Fogle, Jonathan Edward en_US
dc.date.accessioned 2010-04-02T18:28:22Z
dc.date.available 2010-04-02T18:28:22Z
dc.date.issued 2009-01-07 en_US
dc.identifier.other etd-11182008-161051 en_US
dc.identifier.uri http://www.lib.ncsu.edu/resolver/1840.16/3250
dc.description.abstract BSTRACT 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. en_US
dc.rights I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dis sertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to NC State University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. en_US
dc.subject T regulatory cell en_US
dc.subject FIV en_US
dc.subject CD8+ lymphocyte en_US
dc.subject AIDS en_US
dc.title T regulatory Cell Suppression of CD8+ Lymphocyte Responses During FIV Infection. en_US
dc.degree.name PhD en_US
dc.degree.level dissertation en_US
dc.degree.discipline Immunology en_US


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