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Epinephrine Production in Th17 Cells and Experimental Autoimmune Encephalitis.

ABSTRACT: Epinephrine is a hormone secreted primarily by medullary cells of the adrenal glands which regulates permeability of blood-brain barrier (BBB). Recent studies showed signaling by epinephrine/epinephrine receptor in T cells is involved in autoimmune diseases. Nevertheless, the production of epinephrine by T cells and its pathogenic function in T cells are not well investigated. Our results show that phenylethanol N-methyltransferase (PNMT), a rate-limiting enzyme of epinephrine synthesis, is specifically expressed in vitro in differentiated T_H17 cells and in tissue-resident T_H17 cells. Indeed, expression levels of enzymes involved in epinephrine production are higher in T_H17 cells from animals after EAE induction. The induction of PNMT was not observed in other effector T cell subsets or regulatory T cells. Epinephrine producing T_H17 cells exhibit co-expression of GM-CSF, suggesting they are pathogenic T_H17 cells. To delineate the function of epinephrine-production in T_H17 cells, we generated a T_H17-specific knockout of tyrosine hydroxylase (Th) by breeding a Th-flox and a ROR-gt-CRE mouse (Th-CKO). Th-CKO mice are developmentally normal with an equivalent T lymphocyte number in peripheral lymphoid organs. Th-CKO mice also show an equivalent number of T_H17 cells in vivo and following in vitro differentiation. To test whether epinephrine-producing T_H17 cells are key for breaching the BBB, migration of T cells through mouse brain endothelial cells was investigated in vitro. Both epi+ wild-type and epi- T_H17 cells migrate through an endothelial cell barrier. Mice were immunized with MOG peptide to induce experimental autoimmune encephalitis (EAE) and disease progression was monitored. Although there is a reduced infiltration of CD4+ T cells in Th-CKO mice, no difference in clinical score was observed between Th-CKO and wild-type control mice. Increased neutrophils were observed in the central nervous system of Th-CKO mice, suggesting an alternative pathway to EAE progression in the absence of T_H17 derived epinephrine.

SUBMITTER: Yang P

PROVIDER: S-EPMC7937652 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Epinephrine Production in Th17 Cells and Experimental Autoimmune Encephalitis.

Yang Pinguang P Tian Hong H Zou Yong-Rui YR Chambon Pierre P Ichinose Hiroshi H Honig Gerard G Diamond Betty B Kim Sun Jung SJ

Frontiers in immunology 20210222

Epinephrine is a hormone secreted primarily by medullary cells of the adrenal glands which regulates permeability of blood-brain barrier (BBB). Recent studies showed signaling by epinephrine/epinephrine receptor in T cells is involved in autoimmune diseases. Nevertheless, the production of epinephrine by T cells and its pathogenic function in T cells are not well investigated. Our results show that phenylethanol N-methyltransferase (PNMT), a rate-limiting enzyme of epinephrine synthesis, is spec ...[more]

PMID: 33692790

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Project description:BackgroundThere is consensus that experimental autoimmune encephalomyelitis (EAE) can be mediated by myelin specific T cells of Th1 as well as of Th17 phenotype, but the contribution of either subset to the pathogenic process has remained controversial. In this report, we compare functional differences and pathogenic potential of "monoclonal" T cell lines that recognize myelin oligodendrocyte glycoprotein (MOG) with the same transgenic TCR but are distinguished by an IFN-? producing Th1-like and IL-17 producing Th17-like cytokine signature.Methods and findingsCD4+ T cell lines were derived from the transgenic mouse strain 2D2, which expresses a TCR recognizing MOG peptide 35-55 in the context of I-A(b). Adoptive transfer of Th1 cells into lymphopenic (Rag2?/?) recipients, predominantly induced "classic" paralytic EAE, whereas Th17 cells mediated "atypical" ataxic EAE in approximately 50% of the recipient animals. Combination of Th1 and Th17 cells potentiated the encephalitogenicity inducing classical EAE exclusively. Th1 and Th17 mediated EAE lesions differed in their composition but not in their localization within the CNS. While Th1 lesions contained IFN-?, but no IL-17 producing T cells, the T cells in Th17 lesions showed plasticity, substantially converting to IFN-? producing Th1-like cells. Th1 and Th17 cells differed drastically by their lytic potential. Th1 but not Th17 cells lysed autoantigen presenting astrocytes and fibroblasts in vitro in a contact-dependent manner. In contrast, Th17 cells acquired cytotoxic potential only after antigenic stimulation and conversion to IFN-? producing Th1 phenotype.ConclusionsOur data demonstrate that both Th1 and Th17 lineages possess the ability to induce CNS autoimmunity but can function with complementary as well as differential pathogenic mechanisms. We propose that Th17-like cells producing IL-17 are required for the generation of atypical EAE whereas IFN-? producing Th1 cells induce classical EAE.

Dataset Information

Epinephrine Production in Th17 Cells and Experimental Autoimmune Encephalitis.

Publications

Epinephrine Production in Th17 Cells and Experimental Autoimmune Encephalitis.

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