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PROSPECT Report Summary

Project ID: 281365
Funded under: FP7-IDEAS-ERC
Country: Switzerland

Final Report Summary - PROSPECT (Role of Professional and Non-professional Antigen Presenting Cells In Autoimmunity and Cancer)

Our immune system has evolved to efficiently eradicate invading pathogens while remaining tolerant towards our self-tissues. A first checkpoint occurs in the thymus where functional T cells recognizing foreign organism are selected whereas T cells recognizing our self-tissues, called self-reactive T cells, are eliminated. However, this process, called central T cell tolerance, is not perfect, and some self-reactive T cells can be found among our pool of T cells. That is why additional mechanisms, namely peripheral T cell tolerance mechanisms, exist to inactivate/eliminate these self-reactive T cells and avoid the development of autoimmune diseases. Among the cells involved in peripheral T cell tolerance, conventional dendritic cells (cDCs) are extensively implicated since in absence of infection or inflammation, those cells can control self-reactive T cells. Recently however, it appeared that cDCs are not the only players involved in peripheral T cell tolerance. Notably, a particular subset of DCs, the plasmacytoid DCs (pDCs), first thought to function only as producers of inflammatory factors upon viral infections, were demonstrated to contribute as well. In the lab, we are investigating the impact of pDC functions on T cell responses during autoimmunity, such as mouse models of multiple sclerosis (MS). We have found that depending on the inflammatory environment, pDCs can induce very different T cell functions. In particular, we have published that pDCs dampen T cell self-reactivity during central-nervous system autoimmune reaction. In contrast, given the appropriate stimulus, pDCs can behave as efficient activators of T cell responses, and can be exploited for anti-tumor immunotherapies. We are currently working on the molecular mechanisms accounting for differential pDC ability to impact T cell responses. An alternative mechanism of peripheral T cell tolerance, involving non-hematopoietic lymph node stromal cells (LNSCs), has recently emerged. These cells were initially thought to only play a role in organ architecture and in promoting immune cell interactions. However, recent research suggested LNSCs directly impact T cell responses and promote self-specific T cell tolerance. In agreement, we recently published that LNSCs acquire from cDCs the molecular machinery required to inactivate self-reactive T cells, thus contributing to T cell tolerance. We are now investigating the contribution of LNSCs in impacting T cell responses in different pathological settings, such as autoimmunity and cancers.

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