Project

Discipline

T lymphocyte; dendritic cell; self-tolerance; mouse models; autoimmune diseases; intravital imaging; experimental autoimmune encephalomyelitis; lymphoid organs; brain; plasmacytoid dendritic cells; autoimmunity; immune tolerance; T cell activation; mouse model; multiple sclerosis

Lead
Lay summary
The main mediators of adaptive immunity are B and T lymphocytes, but their function is under the control of dendritic cells (DC). DC in the periphery capture and process antigens (Ag), express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to Ag that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. It has become increasingly evident that these cells are powerful tools for manipulating the immune system. DC are generally classified as either conventional (cDC) or plasmacytoid (pDC) DC. It is well established that cDC function as sentinels of the adaptive immune system. They reside in peripheral tissues, sample their surroundings and migrate to secondary lymphoid tissues to present foreign or host Ag to T cells. Under neutral or non-inflammatory conditions, cDC are, paradoxically, able to induce initially a transient activation of host Ag-specific T cells followed by a rapid shutdown of these T cells resulting in tolerance. Inflammatory immune responses, however, cause DC maturation and results in rapid and effective T cell responses. In contrast to cDC, pDC were initially believed to be involved primarily in innate, or first-line, immune responses via the secretion of type I interferons following viral or bacterial infections. However, very recent findings demonstrate that like cDC, pDC are also implicated in adaptive immune responses. Exciting new developments in pDC biology further implicates these cells directly in the induction of T cell tolerance, a key process in avoiding autoimmunity. These processes are at the infancy of being elucidated and further work will potentially open new avenues to the therapeutic treatment, via pDC manipulation, in the aim of controlling debilitating autoimmune diseases. This proposal will allow the intricate in vivo analysis of the impact on immune responses following the selective loss of Ag presentation function by pDC. This work, therefore, entails the use of cutting edge techniques (including two-photon intravital imaging on live animals) and animal models of disease (e.g. multiple sclerosis, autoimmune diabetes) to dissect the mechanisms that allow for pDC-induced T cell tolerance and, thus, protect the host from autoimmunity.

Direct link to Lay Summary

Last update: 21.02.2013

The main mediators of immunity are B and T lymphocytes, but their function is under the control of dendritic cells (DC). DC in the periphery capture and process antigens (Ag), express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to Ag that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Once a neglected cell type, DC can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis. It has become increasingly evident that these cells are a powerful tool for manipulating the immune system. DC are generally classified as either conventional (cDC) or plasmacytoid (pDC). It is well established that cDC function as sentinels of the adaptive immune system. They reside in peripheral tissues, sample their surroundings and migrate to secondary lymphoid tissues to present foreign or host Ag to T cells. Under neutral or non-inflammatory conditions, cDC are, paradoxically, able to induce initially a transient activation of host Ag-specific T cells followed by a rapid shutdown of these T cells resulting in tolerance. Inflammatory immune responses, however, cause DC maturation and results in rapid and effective T cell responses. In contrast to cDC, pDC were initially believed to be involved primarily in innate, or first-line, immune responses via the secretion of type I interferons following viral or bacterial infections. However, very recent findings demonstrate that like cDC, pDC are also implicated in adaptive immune responses. Exciting new developments in pDC biology further implicates these cells directly in the induction of T cell tolerance, a key process in avoiding autoimmunity. Thus, nature has developed a unique system of whereby the hosts immune response, via pDC, present Ag to potentially autoimmune-inducing T cells in order for them to be rendered anergic or non-responsive. These processes are at the infancy of being elucidated and further work will potentially open new avenues to the therapeutic treatment, via pDC manipulation, in the aim of controlling debilitating autoimmune diseases. This proposal will allow the intricate in vivo analysis of the impact on immune responses following the selective loss of Ag presentation function by pDC. This work, therefore, entails the use of cutting edge techniques (including two-photon intravital imaging on live animals) and animal models of disease (e.g. multiple sclerosis, autoimmune diabetes) to dissect the mechanisms that allow for pDC-induced T cell tolerance and, thus, protect the host from autoimmunity. In particular, the pDC involvement in the generation and maintenance of a tolerogenic state in diseases will be investigated. The mechanisms that allow for pDC-induced T cell tolerance and, thus, protect the host from autoimmunity, will be dissected. In particular, the pDC involvement in the generation and maintenance of a tolerogenic state in diseases will be investigated. pDC tolerogenic properties will be carefully analyzed in term of DC phenotype, in vivo DC-T cell interaction dynamics, and T cell outcome and compared to cDC. The contribution/cooperation of both DC subsets in the induction/maintenance of tolerance towards self-antigens will be investigated in vivo using different mouse models for autoimmune diseases. This work entails the use of cutting edge techniques (including two-photon intravital imaging on live animals) and animal models of disease (e.g. multiple sclerosis, autoimmune diabetes). The main objective of this study, therefore, is to define new molecular and cellular biomarkers of pDC activity and, thus, identify potential therapeutic targets for manipulating the immune system in the treatment of debilitating autoimmune diseases. A further long-term objective of the proposal is to expand these studies into oncology and to understand why some tumors are not efficiently eradicated by the immune system. Indeed, by manipulating the pDC responses in tumor models, this project may provide insights into mechanisms to ameliorate current cancer immunotherapy. This work will give a better understanding on the specific subtypes of dendritic cells competent to induce T cell tolerance. An immediate consequence is that vaccination protocols using dendritic cells for cancer treatments should be defined carefully by taking the tolerogenic potential of pDC in account.