The first ideas leading to The Two-Signal Model of lymphocyte activation were published 50 years ago, but the model was not realized in one sitting. I describe the three phases that led to its contemporary formulations. A motivation underlying all these models was to generate a minimal description of what is required for antigen to inactivate and activate mature lymphocytes that, at the same time, accounts for how peripheral tolerance is achieved. I suggest the two signal model has not only provided a substantiated framework for understanding how antigen interacts differently with B cells and CD8 T cells, to result in their inactivation and activation, but its postulates are pertinent to contemporary issues concerning the inactivation and activation of CD4 T cells.
Keywords: T cells; autoimmunity; cell activation; cells; costimulation; processes; tolerance/suppression/anergy.
© 2019 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Foundation for the Scandinavian Journal of Immunology.