Notch signaling regulates T cell accumulation and function in the central nervous system during experimental autoimmune encephalomyelitis.
J Immunol
; 191(4): 1606-13, 2013 Aug 15.
Article
em En
| MEDLINE
| ID: mdl-23825310
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-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 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-γ 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Subpopulações de Linfócitos T
/
Encefalomielite Autoimune Experimental
/
Receptores Notch
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article