title: 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-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.
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Sandy
authors.forename: Josh
authors.initials: J
authors.lastname: Stoolman
authors.forename: Kelli
authors.initials: K
authors.lastname: Malott
authors.forename: Prae
authors.initials: P
authors.lastname: Pongtornpipat
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Segal
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002464:Cell Migration Inhibition; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology; D002633:Chemotaxis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011828:Radiation Chimera; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D000098815:T-bet Transcription Factor
chemical_list: D020381:Interleukin-17; C577863:Mamld1 protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma