T cell activation is a key event in triggering an antigen specific immune response of the organism. The process is induced primarily by the signal generated by direct interaction of a T cell receptor with an antigen bound to the major histocompatibile complex on an antigen-presenting cell (APC). Although the signal is critical in exciting immune response, an additional, costimulating signal is required. The major second signal is generated by interaction of the CD28 molecule expressed on most T lymphocytes with its natural ligands CD80 and CD86 located on APCs. The signal excited by CD28 triggering involves multiple second-messenger cascades, leading to the activation of transcription factors and finally results in cell proliferation, cytokine production, and the generation of effector functions. The importance of CD28-delivered costimulatory signals was proven in experiments with CD28-deficient mice. T cells from these mice exhibited an impaired pattern of cytokine secretion and defects in T cell-dependent antibody production. Certain forms of immunopathology might result from the aberrant regulation of CD28 expression.