3. Regulatory T cells
Regulatory T cells, or Tregs, are a subset of CD4+ lymphocytes specialized in the suppression of immune responses. They are required to prevent the development of auto-immune diseases, but in mice they were also shown to contribute to cancer progression by inhibiting anti-tumor immune responses. Tregs could play a negative role in cancer patients, but this has remained difficult to verify due to the lack of a Treg-specific marker in humans, as well as to an incomplete understanding of the mechanisms underlying their suppressive function.
Our objective is twofold: develop tools to quantify Tregs in human tissues, and identify mechanisms important for their suppressive function, which could be specifically targeted to improve the efficiency of cancer vaccines.
Our previous work lead to the obtention of stable human Treg clones, representing long-term cultures of pure lymphocyte populations available for repeated analysis. A stable epigenetic mark unambiguously distinguished human Treg clones from non regulatory CD4+ (Thelper) or CD8+ (cytolytic) clones: a conserved region in intron 1 of gene FOXP3, encoding a transcription factor indispensable for the development and function of Tregs, was found demethylated in Treg clones only. We set up a real-time PCR assay to quantify demethylated FOXP3 sequences, indicative of the presence of Treg cells. We will use this assay to monitor the distribution of Treg cells in fragments of human tumors. This analysis should contribute to evaluate their role in inhibition of spontaneous or vaccine-induced anti-tumor immune responses.
We also used expression microarrays to compare Treg and Thelper clones after activation, which is required for the suppressive function. This analysis revealed that the hallmark of activated human Treg clones is to produce bioactive TGFβ, which has paracrine and autocrine actions on neighboring T cells.
TGFβ is an immunosuppressive cytokine that is produced by many cell types in a latent, inactive form. We are currently attempting to identify the mechanisms by which Tregs, but not T helper cells, can transform latent TGFβ into the bioactive cytokine. We will also analyze the consequences of TGFβ signaling on the effector function of human T helper or cytolytic T cells. Finally, we will try to define the mechanisms of resistance to TGFβ that characterizes some T helper lymphocytes.
To know more... (pdf chapter of the last de Duve Institute report)
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