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NOVARIPP Report Summary

Project ID: 334763
Funded under: FP7-IDEAS-ERC
Country: Spain

Mid-Term Report Summary - NOVARIPP (Novel properties of antigen receptors and instruments to modulate lymphoid function in physiological and pathological conditions)

One of the major objectives of the project was to study the puzzling properties of the T cell antigen receptors (TCR) in terms of sensitivity and specificity while having a marked component of self-reactivity. Building upon our previous data showing that the TCR is not expressed as an isolated receptor but forms oligomers of up to 20 TCRs we have now found that the pre-formed TCR oligomers, termed nanoclusters signal in a coordinated fashion even if only a few of the individual TCRs are bound to antigen. We show that TCRs crosstalk within nanoclusters, exerting a strong cooperativity detected in the properties of binding to the ligand. Antigen ligand binding to a few TCRs makes these TCRs, and all TCRs in the nanoclusters even if unbound to antigen, to adopt the Active signaling-competent conformation. However, the positive cooperativity effect reaches a maximum 4-8 minutes after the first antigen binding events to decline steeply afterwards. Using antibodies against different subunits of the TCR and fluorescent resonance energy transfer (FRET) methods we demonstrate that positive cooperativity results from a change in the quaternary structure of the TCR nanoclusters that is reverted after the time optimum. We propose that the transient cooperativity effect is a mechanism for signal amplification that allows T cells to count antigen and time.
Other major objectives of the project involved the study of the involvement of the GTPase TC21/RRas2 in the normal function of T and B cells and in their transformation to lymphomas and leukemias. We have found that TC21 is required for the generation of antibodies of high affinity because it is required to sustain the growing energy demands of B cells during the germinal center reaction. TC21 connects signals emanating from the B cell antigen receptor (BCR) and the CD40 costimulatory receptor with the control of B cell metabolism. In the absence of TC21 the generation of ATP by oxidative respiration and by glycolysis is simultaneously impaired. The upregulation of lymphocyte metabolism by TC21 might also be behind the strong driver effect of an oncogenic mutation in TC21. After expression of this mutant in adult mouse tissues 100% of mice develop thymic lymphomas in less than 8 weeks, in addition to other tumors of the female and male reproductive tracts. These findings indicate that an excess of TC21 activity might be important for a variety of human tumors that express an activating mutation of TC21 or overexpress the wild type form. To assess the relevance of TC21 in a clinical setting we are also developing TC21 inhibitors using a structure-activity relationship (SAR)-guided process. We already have compounds that inhibit the growth of TC21-dependent human tumors at concentrations as low as 10 nM in vitro and that can inhibit tumor growth in a xenograft model by 33%. We are still performing additional chemical modifications to improve these numbers.

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