T cell dependent antibodies (Ab) against the muscle acetylcholine receptor (AcHR) cause the symptoms of myasthenia gravis (MG) and experimental MG (EMG). C57Bl/6 (B6) mice develop EMG after subcutaneous (s.c.) immunization with Torpedo AchR (TAChR) in Freund's adjuvant (FA): this primes anti-TAChR CD4+ Th1 cells which induce pathogenic anti-TAChR Ab that bind complement, and cause destruction of the muscle synapses. Nasal administration of soluble TAChR peptides forming CD4+ T cell epitopes protected B6 mice from EMG after immunization with TAChR/FA. CD4+ T cells from mice treated nasally with TAChR epitopes transferred protection from EMG to untreated mice.We wish to test the hypothesis that protection from EMG after nasal exposure to TAChR epitopes requires activation of epitope-specific CD4+ T regulatory (Tr) cells, which modify the outcome of the sensitization of CD4+ T cells and B cells after TAChR/FA immunization. We will use wild type (WT) B6 mice: their anti-TAChR CD4+ T cells recognize a dominant epitope within residues 150-160 of the TAChR alpha subunit. We will use also transgenic B6 mice which express a TCR specific for the TAChR epitope a150-160 in their CD4+ T cells (T-alpha-TCR mice); or the TAChR a subunit in their muscles (T-alpha mice). We will use also B6 null mutants of genes encoding proteins involved in immune signaling.
The specific aims will be:
AIM 1. To identify the phenotype of TAChR-specific CD4+ Tr cells that mediate nasal protection from EMG.
AIM 2. To determine the costimulatory signals and cytokines involved in nasal activation of TAChR-specific CD4+ Tr cells.
AIM 3. To determine the effector mechanisms of the CD4+ Tr cells primed by nasally administered TAChR peptide epitopes.
AIM 4. To determine where the protective CD4+ Tr cells are sensitized and migrate, and whether they affect the proliferation, survival, trafficking and cytokine secretion of anti-TAChR CD4+ T cells primed by the TAChR/FA immunization.These studies will identify the characteristics, and the mechanisms of activation and action of Ag-specific CD4+ Tr cells, which prevent an Ab-mediated autoimmune disease. They may identify new types and protective mechanisms of CD4+Tr cells, other than those at work in the control of T cell-mediated diseases. This will be important to understand both mucosal tolerance and the mechanism of tolerance in general.
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