MS is a chronic autoimmune disease of the CNS in which pro-inflammatory T helper 17 (Thi7) cells are increased. Tri type regulatory T cells (Tregs) are important in peripheral tolerance, act via IL-10, and are deficient in MS. The basic immune mechanisms underlying abnormalities in Teffector/Tregulatory networks in humans and patients with MS are not well understood. We found an important role for IL-27 and the aryl hydrocarbon receptor (AhR) in these networks and the focus of this portion of the Program Project Grant is to investigate these pathways in humans and MS patients. In this revised application we have included the study of other disease controls and the study of cells within the CNS. We will address the following aims:
Aim 1 : Role of IL-27 in the regulation of Th17 and Tr1 cell differentiation in humans. IL-27 plays an important role in inducing IL-10 from murine and human T cells. In addition, we found that AhR activation induces regulatory Tri-like cells both in mice and humans. Furthermore, we found that IL-27 derived Tri cells produce IL-21 which acts as a autocrine growth factor for both Tri and Th17 cells in mice. We will investigate the role of AhR/cMAF signaling in the differentiation of human Tri cells triggered by IL-27 or IL- 27 plus TGFB. We will also study the production and role of IL-21/1L-2 in IL-27 or IL-27 plus TGFB induced Tri cells.
Aim 2 : Role of AhR in innate immunity. We have shown that AhR induces tolerogenic DCs in mice that promote regulatory T cell differentiation and that IFN-p increases expression of IL-27 in murine DCs which increases the expression of AhR in murine T cells. We will investigate the effect of AhR activation in DCs in humans and determine the synergistic effect of AhR activation in the presence of IFN-p on the function and activation of human mDCs.
Aim 3 : IL-27 and AhR in Th17/Tr1 cells and DCs in Multiple Sclerosis. Both AhR and IL-27 signaling are involved in induction of Tri cells and tolerogenic DCs. We will investigate AhR /IL-27 signaling and how it influences Th17 responses in MS, its role in the differentiation of naive T cells to Tri cells and in the induction of tolerogenic DCs in MS patients. We will also investigate how these pathways differ in the various stages of MS and how are they are affected by response to immunotherapy in MS patients.
Our investigations are designed to provide a better basic understanding of immune abnormalities in multiple sclerosis and allow both the development of more specific immunomodulatory therapy and a mechanistic understanding of current therapies being used to treat MS.
|Aschenbrenner, Dominik; Foglierini, Mathilde; Jarrossay, David et al. (2018) An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells. Nat Immunol 19:1126-1136|
|Meyer Zu Horste, Gerd; Przybylski, Dariusz; Schramm, Markus A et al. (2018) Fas Promotes T Helper 17 Cell Differentiation and Inhibits T Helper 1 Cell Development by Binding and Sequestering Transcription Factor STAT1. Immunity 48:556-569.e7|
|Joller, Nicole; Kuchroo, Vijay K (2017) Tim-3, Lag-3, and TIGIT. Curr Top Microbiol Immunol 410:127-156|
|Karwacz, Katarzyna; Miraldi, Emily R; Pokrovskii, Maria et al. (2017) Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation. Nat Immunol 18:412-421|
|Hu, Dan; Notarbartolo, Samuele; Croonenborghs, Tom et al. (2017) Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis. Nat Commun 8:1600|
|Anderson, Ana C; Joller, Nicole; Kuchroo, Vijay K (2016) Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 44:989-1004|
|Meyer Zu Horste, Gerd; Wu, Chuan; Wang, Chao et al. (2016) RBPJ Controls Development of Pathogenic Th17 Cells by Regulating IL-23 Receptor Expression. Cell Rep 16:392-404|
|Mayo, Lior; Cunha, Andre Pires Da; Madi, Asaf et al. (2016) IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation. Brain 139:1939-57|
|Chihara, Norio; Madi, Asaf; Karwacz, Katarzyna et al. (2016) Differentiation and Characterization of Tr1 Cells. Curr Protoc Immunol 113:3.27.1-3.27.10|
|Gaublomme, Jellert T; Yosef, Nir; Lee, Youjin et al. (2015) Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell 163:1400-12|
Showing the most recent 10 out of 18 publications