Dr. Remi Creusot's Research
Immune tolerance and autoimmunity: a brief introduction
Immune tolerance is a process by which the body eliminates or suppresses T cells that may react against self or innocuous environmental antigens. Defects in immune tolerance can lead to autoimmune or allergic disorders. In the case of Type 1 diabetes (T1D) for example, T cells reactive to pancreatic islet antigens are not sufficiently eliminated and/or controlled. The role of eliminating or educating self-reactive T cells is normally fulfilled by specialized “tolerogenic” cells that coexist with immune cells within the thymus, the lymph nodes and the spleen. These cells are referred to as tolerogenic because of two important properties: (1) the ability to present self-antigens (either expressed endogenously or acquired from their surrounding environment) and, as a consequence, to form antigen-specific contacts with self-reactive T cells, and (2) the ability to deliver tolerogenic signals that will cause the deletion or inhibition of those self-reactive T cells, or the induction of suppressive – rather than destructive – functions within those self-reactive T cells. During their development in the thymus, self-reactive T cells have an opportunity to recognize their self-antigens on tolerogenic cells and be adequately dealt with before they can be released into the periphery. Thus, many potentially self-reactive T cells, while in the thymus, can be eliminated or converted into regulatory T cells, which block other self-reactive T cells and protect our tissues from autoimmunity. This process is not perfect, even in healthy individual: some self-reactive T cells escape this selection process and get a step closer to reacting against self-tissues. Fortunately, they get to meet additional tolerogenic cells along the way, as they circulate in our body through lymph nodes and spleen.
Tolerogenic cells comprise two types of cells:
1) Immature dendritic cells: they can exogenously acquire self-antigens in tissues and transport them to lymphoid tissues for presentation. They are considered professional antigen-presenting cells as they can become “immunogenic” upon maturation in the context of inflammation or infection. They therefore constitute double-edge swords that can both prevent and induce autoimmunity. Whether or not these cells can also endogenously express tissue-specific self-antigens remains controversial.
2) Stromal cells: these are non-professional antigen-presenting cells with limited antigen-presentation capabilities. They are unable to process exogenous antigens and mount immune responses. However, some of them have the capacity to ectopically express tissue-specific antigens at low levels, and possess many tolerogenic tools to induce tolerance.
Particular stromal cells in the thymus have the ability to express tissue-specific antigens, which is conferred by the function of AIRE. The importance of this process is demonstrated by the observation that AIRE-deficiency in both humans and mice leads to a severe autoimmune syndrome targeting multiple tissues (T1D is observed in ~20% of cases). We have recently discovered that ectopic expression of tissue-specific antigens can also be regulated by DEAF1, a regulator of gene expression that has some homologies with AIRE. In both T1D patients and NOD mouse model of T1D, the progression of disease is associated with a defective function of DEAF1 due the alternative mRNA splicing in the pancreatic lymph nodes. In the case of T1D, this particular tissue is central, both a major site of disease initiation and a site of competition between tolerogenic and immunogenic signals for islet antigens. Thus inability of tolerogenic cells to ectopically express tissue-specific antigens in this tissue can tip the balance in favor of immunogenic / diabetogenic responses.
- Although DEAF1 is widely expressed as opposed to AIRE, it has unique functions that are dependent on the cell types in which it is expressed. We are particularly interested in studying the role and function of DEAF1 in tolerogenic cells, and the relevance of its association with T1D. Both the NOD mouse model of T1D and human lymphoid tissues are used in our studies.
- Distinct populations of tolerogenic cells, stromal or dendritic, are unique in the tolerogenic molecules and pathways that they utilize to mediate immune tolerance, resulting in different outcomes. We designed a platform to recreate different “tolerogenic interfaces”, either naturally occurring or employing novel combinations, to study how these different signals are perceived and integrated by self-reactive T cells and to determine the outcome of this interaction.
- T1D is a complex disease, wherein the causes leading to loss of tolerance are both numerous and variable between individuals (in humans). The ever-increasing incidence of disease in Western countries calls for a better understanding of the environmental factors that contribute to this alarming trend. We have identified new potential factors that could impact the prevalence of disease and are exploring the mechanisms of action.
Shamael Dastagir, MA
Chunliang Xu, PhD
Creusot RJ, Yaghoubi SS, Kodama K, Dang DN, Dang VH, Breckpot K, Thielemans K, Gambhir SS, Fathman CG. Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice. Clin. Immunol. (2008) 127(2):176-187.
Kodama K, Butte AJ, Creusot RJ, Su L, Sheng D, Dang D, Hartnett M, Iwai H, Holness C, Soares LR, Fathman CG. Time-dependent and tissue-specific changes in gene expression during disease induction and progression in NOD mice. Clin. Immunol. (2008) 129(2):195-201.
Creusot RJ, Yaghoubi SS, Chang P, Chia J, Contag CH, Gambhir SS, Fathman CG. Lymphoid tissue specific homing of bone marrow-derived dendritic cells. Blood (2009) 113(26):6638-6647.
Yip L, Su L, Sheng D, Chang P, Atkinson M, Czesak M, Albert PR, Collier A, Turley SJ, Fathman CG, Creusot RJ. Deaf1 isoforms control peripheral tissue antigen expression in the pancreatic lymph nodes during type 1 diabetes. Nature Immunol. (2009) 10(9): 1026-1033.
Creusot RJ, Chang P, Healey DG, Tcherepanova IY, Nicolette CA, Fathman CG. A short pulse of IL-4 delivered by DCs electroporated with modified mRNA can both prevent and treat autoimmune diabetes in NOD mice. Mol. Ther. (2010) 18(12): 2112-2120.
Yip L, Creusot RJ, Pager CT, Sarnow P, Fathman CG. Reduced DEAF1 function during Type 1 diabetes inhibits translation in lymph node stromal cells by suppressing Eif4g3. J. Mol. Cell. Biol. (2012) [Epub Aug 24].
Junttila IS*, Creusot RJ*, Moraga I*, Bates DL*, Wong MT, Alonso MN, Suhoski MM, Lupardus P, Meier-Schellersheim M, Engleman EG, Utz PJ, Fathman CG, Paul WE, Garcia KC. Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines. Nature Chem. Biol. (2012) 8(12): 990-998. (*Contributed equally)