Community Research and Development Information Service - CORDIS



Project ID: 250289
Funded under: FP7-IDEAS-ERC
Country: Switzerland

Final Report Summary - TERRAINCOGNITA (T cell receptor αβ : in control of signal initiation and T cell fate)

In every individual, T cells develop in the thymus, an organ located above the heart. In a human, more than 100 billion T cells are generated and each developing T cell expresses a unique T cell receptor (TCR). This enormous diversity of TCRs allows the organism to respond to a wide variety of different pathogens, but as many as 10% of newly generated TCRs are autoimmune. This inevitable generation of autoimmune TCRs places the individual at risk of developing a fatal autoimmunity. This dilemma seems to have been “solved” by the evolution of two selective processes. Developing T cells, weakly binding normal cellular components (using low affinity TCRs) are permitted to continue their maturation. This process is called positive selection, generating mature T cells, which migrate out of the thymus and participate in the host’s defense against infections. In contrast, developing T cells that strongly bind normal cellular components (using high affinity TCRs) undergo cell death. This mechanism, called negative selection, eliminates the majority of autoimmune T cells before they mature. Through negative selection, the immune system becomes self-tolerant. The TCR is almost unique among cell surface receptors — depending on the strength of binding to a molecule in the body (self-antigen) the TCR can transduce two different kinds of signals (positive or negative selection) and direct two different T cell fates (continued differentiation or cell death).
With the support of this ERC Advanced grant, we have finally understood how the TCR receptor is able to carry out this balancing act. This has been one of the dilemmas in understanding how the immune system functions. We have also investigated the fundamental characteristics of autoimmune T cells and identified the TCR affinity which is most likely to cause an autoimmune disease. Using an experimental model system, we determined the minimum number of T cells required to initiate an autoimmune disease. We also identified two key populations of regulatory T cells: one population helps maintain conventional T cells in a relatively quiescent state and the second population maintains an immunological balance in the colon, lowering the risk to develop colitis.

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