title: Production of neurotrophins by activated T cells: implications for neuroprotective autoimmunity.
abstract: Neurotrophins (NTs) promote neuronal survival and maintenance during development and after injury. However, their role in the communication between the nervous system and the immune system is not yet clear. We observed recently that passively transferred activated T cells of various antigen specificities home to the injured central nervous system (CNS), yet only autoimmune T cells specific to a CNS antigen, myelin basic protein (MBP), protect neurons from secondary degeneration after crush injury of the rat optic nerve. Here we examined the involvement of NTs in T-cell-mediated neuroprotection, and the possible significance of the antigen specificity of the T cells in this activity. Analysis of cytokine and NT expression in various rat T cell lines showed that the T cells express mRNA for cytokines of Th1, Th2, and Th3 phenotypes. In addition, the T cells express mRNA and protein specific to nerve growth factor, brain-derived neurotrophic factor, NT-3, and NT-4/5. Antigen activation significantly increased NT secretion. Thus, reactivation of CNS autoimmune T cells by locally presented antigens to which they are specific can lead to enhanced secretion of NTs and possibly also of other factors in injured optic nerves. mRNA for TrkA, TrkB and p75 receptors was expressed in the injured nerve, suggesting that these specific receptors can mediate the effects of the T-cell-derived NTs. The neuroprotective effect of the passively transferred autoimmune anti-MBP T cells in injured optic nerves was significantly decreased after local applicaiton of a tyrosine kinase inhibitor known to be associated with NT-receptor activity. These results suggest that the neuroprotective effect of autoimmune T cells involves the secretion of factors such as NTs by the T cells reactivated by their specific antigen in the injured CNS. T cell intervention in the injured CNS might prove to be a useful means of promoting post-injury CNS maintenance and recovery, possibly via supply of NTs and other factors.
authors.affiliation: Department of Neurobiology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Moalem
authors.forename: A
authors.initials: A
authors.lastname: Gdalyahu
authors.forename: Y
authors.initials: Y
authors.lastname: Shani
authors.forename: U
authors.initials: U
authors.lastname: Otten
authors.forename: P
authors.initials: P
authors.lastname: Lazarovici
authors.forename: I R
authors.initials: IR
authors.lastname: Cohen
authors.forename: M
authors.initials: M
authors.lastname: Schwartz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D007424:Intracellular Fluid / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics; D008969:Molecular Sequence Data; D020932:Nerve Growth Factor / Q000235:genetics; D009414:Nerve Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D018696:Neuroprotective Agents; D020933:Neurotrophin 3 / Q000096:biosynthesis / Q000235:genetics; D009900:Optic Nerve / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D020813:Receptor, trkB
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D008562:Membrane Glycoproteins; D020932:Nerve Growth Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D011505:Protein-Tyrosine Kinases; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor; C071951:neurotrophin 5; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB; C073922:neurotrophin 4