Activation versus Tolerance: A Decision Made by T Helper Cells

Twenty years ago, Peter Bretscher and Mel Cohn proposed the "two signal hypothesis" for lymphocyte activation, which dealt with the ongoing need to maintain self-tolerance in the face of B-cell hypermutation (Bretscher and Cohn 1970). They suggested that a B cell must receive two consecutive signals in order to be activated: Signal 1 from the antigen and Signal 2 from a second cell specific for the same antigen, e.g., a T helper cell (Cohn 1989). Under this model, a B cell that mutates and becomes autoreactive would find itself alone and unable to receive Signal 2, except in those exceedingly rare circumstances where an autoreactive T helper cell arises at the same time and in the same place. Thus, a newly autoreactive B cell, receiving only Signal 1 from the autoantigen, would not respond. The model also went one step farther; to prevent accumulation of autoreactive cells with time, it...