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

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.PHDImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/108991/1/hgrifka_1.pd

IL‐12‐polarized Th1 cells produce GM‐CSF and induce EAE independent of IL‐23

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115966/1/eji3410.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/115966/2/eji3410-sup-0002-PRC.pd

T-bet Expression by Foxp3(+) T Regulatory Cells is Not Essential for Their Suppressive Function in CNS Autoimmune Disease or Colitis

Accumulation of T regulatory (Treg) cells within the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE) is essential for the resolution of disease. CNS Treg cells have been shown to uniformly express the Th1-associated molecules T-bet and CXCR3. Here we report that the expression of T-bet is not required for the function of these Treg within the CNS. Using mice that lacked T-bet expression specifically within the Treg compartment, we demonstrate that there was no deficit in Treg recruitment into the CNS during EAE and no difference in the resolution of disease compared to control mice. T-bet deficiency did not impact on the in vitro suppressive capacity of Treg. Transfer of T-bet-deficient Treg was able to suppress clinical signs of either EAE, or colitis. These observations demonstrate that, although Treg can acquire characteristics associated with pathogenic Teff cells, this process is not necessarily required for their suppressive capacity and the resolution of autoimmune inflammation

GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis

Given that granulocyte macrophage colony-stimulating factor (GM-CSF) is identified as the key factor to endow auto-reactive Th cells with the potential to induce neuroinflammation in experimental autoimmune encephalomyelitis (EAE) models, the frequency and phenotype of GM-CSF-producing (GM-CSF+) Th cells in draining lymph nodes (dLNs) and spinal cord (SC) of Albino Oxford (AO) and Dark Agouti (DA) rats immunized for EAE were examined. The generation of neuroantigen-specific GM-CSF+ Th lymphocytes was impaired in dLNs of AO rats (relatively resistant to EAE induction) compared with their DA counterparts (susceptible to EAE) reflecting impaired CD4+ lymphocyte proliferation and less supportive of GM-CSF+ Th cell differentiation dLN cytokine microenvironment. Immunophenotyping of GM-CSF+ Th cells showed their phenotypic heterogeneity in both strains and revealed lower frequency of IL-17+ IFN-gamma+, IL-17+ IFN-gamma-, and IL-17-IFN-gamma+ cells accompanied by higher frequency of IL-17-IFN-gamma- cells among them in AO than in DA rats. Compared with DA, in AO rats was also found (i) slightly lower surface density of CCR2 (drives accumulation of highly pathogenic GM-CSF+ IFN-gamma+ Th17 cells in SC) on GM-CSF+ IFN-gamma+ Th17 lymphocytes from dLNs, and (ii) diminished CCL2 mRNA expression in SC tissue, suggesting their impaired migration into the SC. Moreover, dLN and SC cytokine environments in AO rats were shown to be less supportive of GM-CSF+ IFN-gamma+ Th17 cell differentiation (judging by lower expression of mRNAs for IL-1 beta, IL-6 and IL-23/p19). In accordance with the (i) lower frequency of GM-CSF+ Th cells in dLNs and SC of AO rats and their lower GM-CSF production, and (ii) impaired CCL2 expression in the SC tissue, the proportion of proinflammatory monocytes among peripheral blood cells and their progeny (CD45(hi) cells) among the SC CD11b+ cells were reduced in AO compared with DA rats. Collectively, the results indicate that the strain specificities in efficacy of several mechanisms controlling (auto) reactive CD4+ lymphocyte expansion/differentiation into the cells with pathogenic phenotype and migration of the latter to the SC contribute to AO rat resistance to EAE

T-bet or not T-bet: Taking the last bow on the autoimmunity stage

The search for the encephalitogenic factor driving pathogenic T cells in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis (MS), and psoriasis has proven to be a long and difficult mission, which is not yet completed. In this issue of the European Journal of Immunology, the importance of the transcription factor T-bet, previously shown to be essential for the induction of autoimmune disease in mice, is challenged. Two independent groups, O'Connor et al. [Eur. J. Immunol. 2013. 43:2818-2823] report] and Grifka-Walk et al. [Eur. J. Immunol. 2013. 43:2824-2831], report that T-bet is not mandatory for T cells to cause experimental autoimmune encephalomyelitis (EAE), which serves as a paradigmatic T-cell-mediated autoimmune disease. Both groups found that T-bet KO mice were fully susceptible to develop EAE, both after immunization with self-antigen and after adoptive transfer of IL-23-polarized autoaggressive T cells. T-bet deficiency mediated the loss of IFN-γ expression but retained or even enhanced GM-CSF and IL-17 production by central nervous system (CNS)-infiltrating T cells. These findings indicate that we have lost the last transcriptional regulator previously held to be required for the generation of autoimmune pathogenic T cells

Gut microbiome dysbiosis drives metabolic dysfunction in Familial dysautonomia

Familial dysautonomia is a rare genetic disease caused in part by neurodegeneration. Here, the authors show that the gut-metabolism axis is altered in both patients and transgenic mice and that disease pathology is ameliorated by controlling microbiome divergence