Cytokine Profiles ofIn VivoActivated Thyroid-Infiltrating T Cells Cloned in the Presence or Absence of Interleukin 4

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Abstract
We compared Th1 and Th2 cytokines secreted by randomly selected, intrathyroidal CD4+ T cell clones isolated from a patient with Graves' disease using IL-4 + IL-2 versus IL-2 alone. Prior to T cell isolation, PCR of cDNA from the intact thyroid tissue generated IL-4 and IL-10, but not IFN-γ, products. As controls, IL-4, IFN-γ and IL-10 cDNA was amplified from stimulated, but not unstimulated, PBMC. All 21 of the nine IL-2 clones and twelve IL-2 + IL-4 clones isolated from the thyroid tissue were CD4+. With the exception of one clone in the IL-2 group, all clones produced IL-10 on stimulation with anti-CD3 and phorbol-12-myristate 13-acetate (PMA) with similar mean values for both groups. The majority of clones in both groups also produced IFN-y and IL-4 after stimulation. However, the IL-4: IFN-γ ratios were significantly higher in clones isolated using IL-2 + IL-4 than in those isolated with IL-2 alone. Furthermore, the distribution of Thl, ThO and Th2 type clones, defined by their IL-4: IFN-γ ratios, was also significantly different between those isolated using IL-2 alone and those isolated using IL-2 + IL-4. Of note, although Th0 clones predominated in both groups, Th1 clones were only obtained using IL-2 alone and Th2 clones were only obtained with IL-2 + IL-4. In conclusion, the presence of IL-4 together with IL-2 induces a shift away from a Th1-towards a Th2-response in T cells cloned from in vivo-activated thyroid-infiltrating lymphocytes. This difference in cytokine profile emphasizes that IL-4 is required for cloning T cells representative of a response involving both Th1 and Th2 cells, as occurs in autoimmune thyroid disease.