Clarifying the Critical Factors for Th1 and Th17 Pathogenicity in an Animal Model of CNS-Targeted Autoimmune Disease.

IL-12 and IL-23 Polarization of CD4+ T Cells;Multiple Sclerosis (MS);Experimental Autoimmune Encephalitomyelitis (EAE);Th1 and Th17 Cells;Th17 Cell Plasticity;Microbiology and Immunology;Health Sciences;Immunology

Walk, Heather M. GrifkaLaouar, Yasmina ;

University of Michigan

关键词: IL-12 and IL-23 Polarization of CD4+ T Cells;    Multiple Sclerosis (MS);    Experimental Autoimmune Encephalitomyelitis (EAE);    Th1 and Th17 Cells;    Th17 Cell Plasticity;    Microbiology and Immunology;    Health Sciences;    Immunology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/108991/hgrifka_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Experimental autoimmune encephalitomyelitis (EAE) is a CD4+ T cell-mediated CNS-targeted autoimmune disease and a model of multiple sclerosis (MS).IL-12-polarized IFN-γ-producing Th1 cells and IL-23-polarized IL-17-producing Th17 cells have been implicated in EAE and MS pathogenesis. However, current dogma states that IL-23, and not IL-12, is absolutely critical for T cell encephalitogenicity. Furthermore, few reports measuring Th1 or Th17 cells in EAE have considered Th17 cell plasticity. IL-23-polarized Th17 cells can downregulate IL-17 and upregulate IFN-γ, which makes them indistinguishable from Th1 cells. This conversion to an ;;exTh17” is T-bet-dependent and promoted by IL-23. Though we have previously demonstrated that IL-12- or IL-23-polarized T cells can each induce EAE via distinct mechanisms, the contribution of IL-23 to IL-12-polarized disease, and vice versa, is unexamined. Therefore, we questioned whether IFN-γ-producing CD4+ T cells found during MS and EAE are actually IL-23-driven exTh17 cells and whether bona fide Th1 or stable Th17 cells are encephalitogenic independently of exTh17 cells. We also questioned whether distinctions seen between IL-12- and IL-23-mediated EAE could be found in MS patients. Here, we used adoptive transfer models of EAE to demonstrate that IL-12-polarized Th1 cell encephalitogenicity can be IL-23-independent.IL-23-independent Th1-mediated disease and IL-12-independent Th17-mediated disease had distinct cellular infiltration patterns and cytokine and chemokine expression profiles. Furthermore, we saw distinct cytokine and chemokine profiles in MS patients grouped by relative IL-12 and IL-23 expression. We also investigated the contribution of plasticity to Th17 pathogenicity. We demonstrated that IL-23-polarized T-bet-/- cells were stable Th17 cells. They induced EAE following adoptive transfer into wild-type and RAG2-/- hosts, though disease was milder and delayed relative to wild type Th17 cells. We also determined that the reduced potency of stable Th17 cells is not a result of poor proliferation or survival, rather due to altered trafficking molecules on stable Th17 cells. These data contribute to the understanding to the critical factors for CD4+ T cell encephalitogenicity, and suggest that Th1, Th17, and exTh17 cells are distinct effector lineages in EAE. These data have translational implications, which could result in the discovery of biomarkers in MS patient populations and targeted therapies.