Mechanisms that regulate pro-inflammatory cytokine expression in CD4+ T cells
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Cytokines released by innate immune cells initiate pathways that drive the differentiation of CD4+ T cells into subsets with defined patterns of cytokine secretion. Type I interferons (IFNs) are cytokines that decrease a virus’s capability to replicate in cells. Prolonged exposure to them, as in chronic viral infections, lead to immune suppression. Little is known about the effects of type I IFNs on cytokine expression by CD4+ T cells. My studies, as described in this thesis, show that the type I IFN, IFNα, can impact cytokine secretion by CD4+ T cells, and timing of IFNα exposure can impact the effect. When isolated mouse CD4+ T cells were pre-treated with IFNα prior to activation, expression of the gene encoding Interleukin-2 (IL-2) significantly increased and expression of the gene encoding IFNγ significantly decreased. When T cell Receptor (TCR) and type I IFN pathways were activated simultaneously, expression of the gene encoding Granulocyte-macrophage colony-stimulating factor (GM-CSF) was decreased. Since timing of IFNα exposure changed the effect, these results demonstrate the sensitivity of the interconnections between the IFNα pathway and pro-inflammatory cytokine expression pathway. These results indicate altered cytokine expression due to prolonged exposure of CD4+ T cells to IFNα as a possible explanation for immune suppression in chronic viral infection. Ikaros is a transcription factor that regulates expression of some pro-inflammatory cytokines. CD4+ T cells that lacked Ikaros expression responded differently to IFNα exposure indicating a possible role for Ikaros in modulating the effect of IFNα on the expression of pro-inflammatory cytokines.