Lymphocyte costimulation via the inducible costimulatory molecule (ICOS) is required for effective humoral immunity development. Following immunization with Torpedo acetylcholine receptor (AChR), ICOS gene knockout (KO) mice were highly resistant to clinical experimental autoimmune myasthenia gravis (EAMG) development, had less serum AChR-specific immunoglobulins (Igs), and exhibited a diminutive germinal center (GC) reaction in secondary lymphoid tissues. Lymphocyte proliferation and both Th1 and Th2 differentiation in response to AChR and the AChR dominant alpha146-162 peptide were inhibited by the ICOS gene deficiency. ICOS-mediated lymphocyte costimulation is thus vital to the induction of T cell-mediated humoral immunity to AChR and the development of clinical EAMG. (C) 2004 Elsevier B.V. All rights reserved.