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Accueil > Research > Main scientific focus areas > Immune tolerance

Immune tolerance


Type 1 diabetes and multiple sclerosis are frequently occurring T cell-mediated organ-specific autoimmune diseases that cause enormous suffering among affected individuals. Today, we are still far from understanding the complex pathogenic mechanisms which are underlying these diseases, and no causal therapeutic approaches and preventative measures have yet been developed. Moreover, it remains elusive how the mechanisms, which prevent autoimmunity in healthy individuals, have been circumvented in patients with an autoimmune disease. All this underlines the strong need to increase our knowledge of the pathological processes that trigger autoimmunity.
 

During T cell development, a large number of T cells bearing auto-reactive T cell receptors are generated. Out of these, T cells with which strongly react to very high auto-antigens reactive potential (high avidity auto-reactive T cells) are effectively eliminated. In contrast, several groups (including us) have shown that T cells which are weakly reactive to self-antigen (low avidity T cells) routinely escape this elimination or silencing (Zehn and Bevan, Immunity 2006; von Herrath and Oldstone, Immunity, 1994; Enouz and Zehn, Journal of Experimental Medicine 2012). These low avidity auto-reactive T cells have the potential to cause life threatening autoimmune diseases but they are normally well tolerated and they remain quiescent. How this state of quiescent is achieved and maintained in healthy individuals (and bypassed in patients) could so far not be addressed, as we lacked suitable experimental systems to study the phenotypic and functional characteristics of low avidity T cells prior to their activation and expansion. We considered it therefore instrumental to develop a robust and well defined experimental system which allows to study low avidity auto-reactive T cells in health and disease (Enouz and Zehn, Journal of Experimental Medicine 2012).
 

Taking advantage of this model, we are now performing cross-over studies in which we utilize the power of small animal models to deconvolve how genetic particularities (i.e. diseases associated single-nucleotide polymorphisms [SNPs]) and environmental conditions (i.e. pathogen infections) promote autoimmunity in humans. Within our project, we make several bi-directional mouse to human connections by investigating both mouse and human T cell responses and by transferring genetic particularities into mice that predispose humans to develop T1D. Presently, we are performing key steps into this direction and intent to intensify such interconnecting research activities in the future. Very critical for successfully making such connections is to use model systems that very well reflect the particularities of human diseases. In the past, experimental systems have often been used which only suboptimally reflect these particularities. In contrast, with the above mentioned model that focuses on low affinity T cells, we are studying the quality of T cells that is most relevant for autoimmune diseases.
 

Moreover, it is well known that immune responses against tumors are mediated by the same type (but different specificity) of low avidity T cells involved in autoimmunity. Thus, by revealing yet unknown mechanisms how tolerance mechanisms that apply to low and immunological quiescence of low avidity T cells is being maintained, we will also gain critical insights gain knowledge how the such quiescence state of tumor-reactive T cells could selectively intentionally and selectively be bypassed with the intention to improve the efficacy of and how the efficacy of therapeutic anti-tumor vaccination can be improved.
 

Overall, our research is therefore equally relevant for the fields of autoimmunity and tumor-therapy and will we aim to provide critical novel new insights to stipulate translational research in both fields.


Selected publications
  • Hebeisen M., Oberle S.G., Presotto D., Speiser D.E., Zehn D. and Rufer N. Molecular insights for optimizing T cell receptor specificity against cancer. Front. Immunol. 2013, 4:154. PubMed
     

  • Enouz S., Carrié L., Merkler D., Bevan M.J. and Zehn D. Autoreactive T cells bypass negative selection and respond to self-antigen stimulation during infection. J. Exp. Med. 2012, 209:1769-1779. PubMed
     

  • Zehn D. and Bevan M.J. T cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity. Immunity. 2006, 25:261-270. PubMed