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Notch signaling regulates T cell accumulation and function in the central nervous system during experimental autoimmune encephalomyelitis.

ABSTRACT: Systemic inhibition of Notch signaling was previously shown to attenuate experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis in mice. Different studies attributed these effects to decreased T-bet and IFN-? expression, enhanced regulatory T cell function, reduced T cell chemotaxis to the CNS, or impaired Th9 cell differentiation. Interpretation of these heterogeneous findings is difficult because past experimental strategies did not ensure complete Notch inhibition in T cells and because many cell populations could be affected by systemic Notch blockade. To resolve the role of Notch in T cells during EAE, we used the pan-Notch inhibitor dominant-negative form of Mastermind-like 1 (DNMAML), as well as several complementary loss-of-function approaches specifically in myelin-reactive T cells. Notch inhibition in T cells profoundly decreased EAE incidence and severity. Notch-deprived myelin-reactive T cells had preserved activation and effector differentiation in secondary lymphoid tissues. However, Notch-deprived T cells failed to accumulate in the CNS after immunization. Parking wild-type and DNMAML T cells together in bone marrow chimeras increased accumulation of Notch-deprived T cells in the CNS after immunization but did not prevent EAE, indicating the absence of dominant suppression by DNMAML T cells. Analysis of CNS-infiltrating DNMAML T cells revealed markedly defective IL-17A and IFN-? production, despite preserved T-bet expression. Collectively, our findings capture the profound overall effects of Notch signaling in myelin-reactive T cells and demonstrate that Notch controls the accumulation and pathogenic functions of CD4(+) T cells within their target organ but not in lymphoid tissues during EAE.

SUBMITTER: Sandy AR

PROVIDER: S-EPMC3735619 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Notch signaling regulates T cell accumulation and function in the central nervous system during experimental autoimmune encephalomyelitis.

Sandy Ashley R AR Stoolman Josh J Malott Kelli K Pongtornpipat Prae P Segal Benjamin M BM Maillard Ivan I

Journal of immunology (Baltimore, Md. : 1950) 20130703 4

Systemic inhibition of Notch signaling was previously shown to attenuate experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis in mice. Different studies attributed these effects to decreased T-bet and IFN-γ expression, enhanced regulatory T cell function, reduced T cell chemotaxis to the CNS, or impaired Th9 cell differentiation. Interpretation of these heterogeneous findings is difficult because past experimental strategies did not ensure complete Notch inhibit ...[more]

PMID: 23825310

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Project description:Neural precursor cell (NPC) transplantation has been proposed as a therapy for multiple sclerosis (MS) and other degenerative disorders of the central nervous system (CNS). NPCs are suggested to exert immune modulation when they are transplanted in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Herein, we explore whether the effect of NPC transplantation on the clinical course and the pathological features of EAE is combined with the modulation of chemokines levels expressed in the inflamed CNS. NPCs were isolated from brains of neonatal C57/Bl6 mice and were subcutaneously administered in female mice with myelin oligodendrocyte glycoprotein (MOG)-induced EAE. Clinical signs of the disease and transcript analysis of the CNS in the acute phase were performed. In addition, the presence of inflammatory components in the spinal cord was evaluated and ex vivo proliferation of lymphocytes was measured. NPC recipients exhibited ameliorated clinical outcome and less pronounced pathological features in their spinal cord. Downregulation of chemokine mRNA levels throughout the CNS was correlated with diminished Mac-3-, CD3-, and CD4-positive cells and reduced expression levels of antigen-presenting molecules in the spinal cord. Moreover, NPC transplantation resulted in lymphocyte-related, although not splenocyte-related, peripheral immunosuppression. We conclude that NPCs ameliorated EAE potentially by modulating the levels of chemokines expressed in the inflamed CNS, thus resulting in the impaired recruitment of immune cells. These findings further contribute to the better understanding of NPCs' immunomodulatory properties in neuroinflammatory disorders, and may lead to faster translation into potential clinical use.Endogenous neural precursor cells of the central nervous system are able to migrate and differentiate toward mature cells to repair an injury. There is increasing evidence that autologous transplantation of these cells in experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis, may have a beneficial effect on the disease process. Several mechanisms have been proposed-among them, the potentiation of endogenous precursor cell differentiation of the central nervous system and the modulation of demyelinating and neurodegenerative immune-mediated processes. This article provides evidence of interference in immune signaling within the central nervous system as a potential mechanism underlying the immunomodulatory properties of transplanted neural precursor cells.

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Dataset Information

Notch signaling regulates T cell accumulation and function in the central nervous system during experimental autoimmune encephalomyelitis.

Publications

Notch signaling regulates T cell accumulation and function in the central nervous system during experimental autoimmune encephalomyelitis.

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