Dr. Remi Creusot's Research
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 beta-cell antigens are not properly eliminated and/or controlled. The role of eliminating or educating self-reactive T cells is normally fulfilled by specialized “tolerogenic” cells that interact with immune cells, primarily 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 circulation. 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, there are additional tolerogenic cells that T cells can later encounter while circulating in the body, and which constitute one of the focuses of the lab.
Tolerogenic antigen-presenting cells comprise two types of cells:
1) Dendritic cells: they can exogenously acquire self-antigens in tissues and transport them to lymphoid tissues for presentation. They exist under two functional modes: tolerogenic or immunogenic. While their immunogenic mode is useful to fight infections and tumors, it is their tolerogenic mode that we aim to understand and exploit.
2) Stromal cells: these are non-professional antigen-presenting cells that are incapable of mounting immune responses, but have the ability to suppress some autoimmune responses.
Particular stromal cells in the thymus have the ability to express tissue-specific antigens, which is conferred by the function of the protein 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 endogenous expression of tissue-specific antigens can also be regulated by DEAF1, a regulator of gene expression that has 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, pancreatic lymph nodes are central, both a major site of disease initiation and a site of competition between tolerogenic and immunogenic cells that present beta-cell antigens. Thus inability of tolerogenic cells to express tissue-specific antigens in this tissue may tip the balance in favor of immunogenic cells eliciting diabetogenic responses.
Ø 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.
Ø 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 study ways to create more powerful tolerogenic cells that can be used to treat T1D by reprograming harmful T cells into protective T cells.
Shamael Dastagir, MA
Chunliang Xu, PhD
James Stoeckle (summer 2013, NIDDK Medical Student Research Program in Diabetes)
William Follis (summer 2014, high school student)
Carmen Matos (summer 2014, rotating graduate student)
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.
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)
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. (2013) 5(2): 99-110.
Creusot RJ, Giannoukakis, N, Trucco M, Clare-Salzler MJ, Fathman CG. It’s time to bring dendritic cell therapy to Type 1 Diabetes. Diabetes (2014) 63(1): 20-30.
Yip L, Fuhlbrigge R, Taylor C, Creusot RJ, Matsumura T, Whiting C, Schartner JM, Akter R, Von Herrath M, Fathman CG. Inflammation and hyperglycemia mediate Deaf1 splicing in the pancreatic lymph nodes via distinct pathways during Type 1 diabetes. Diabetes (2014) In press.