T cell tolerance to AChR, the autoantigen in myasthenia gravis, is mediated primarily by peripheral mechanisms (128.25)

Abstract

Abstract In myasthenia gravis (MG), a T-cell dependent antibody response is directed against acetylcholine receptor (AChR) at the neuromuscular junction. To study T cell tolerance, we generated a transgenic mouse in which the TAChRα chain is expressed as a self protein. This transgenic was bred to nude mice and thymus transplants were performed to produce progeny expressing TAChRα in the thymus and/or the periphery (muscle). These mice were immunized with the TAChRα dominant epitope, p146–162, and in vitro proliferation of responding T cells was measured. Since AChR is expressed at low levels in the thymus, it was presumed that central tolerance would be important. However, this was not the case; only mice with peripheral expression of TAChRα showed tolerance (a lack of proliferation). Furthermore, CFSE-labeled TAChR specific T cells from a TCR transgenic were adoptively transferred into TAChR transgenic (tolerizing) and non-transgenic recipients. Following immunization, proliferation of the transferred T cells was lower in the TAChR transgenic host. Moreover, when the TAChR transgene was bred to scurfy mice, progeny lacking Tregs (foxp3−/Y) exhibited an increase in serum anti-TAChR Ig. Autoantibodies were not seen in the foxp3+/Y mice or in mice lacking Aire function (which have defective central tolerance). These results are consistent with a primary role for peripheral tolerance in regulating the response to AChR. Supported by an APC Subcontract, a UTHSCSA ERC grant and NIH (T32AG021890, T32DE11438).