ABSTRACT
The concept that T cells require two distinct signals for full activation was offered more than
three decades ago. The first signal, antigen recognition, is provided by the interaction
between an MHC/peptide complex on an antigen-presenting cell (APC) and the T-cell receptor (TCR). The second, or costimulatory, signal is provided by the ligation of accessory
molecules expressed on the surface of APC (among other cell types) to counterreceptors
expressed on T cells. T-cell costimulation stabilizes cytokine mRNA, facilitates cell cycle
progression, and induces antiapoptotic proteins, resulting in productive and sustained T-cell
responses (1-3). In the absence of positive costimulatory signals, TCR ligation by the
MHC/peptide complex induces the T cell to become specifically nonresponsive (tolerant) to subsequent MHC/peptide engagement. Jenkins and Schwartz demonstrated that interference with costimulation of T-cell activation in antigen-activated murine T-cell
clones can render these cells incapable of proliferating in response to the relevant antigen
even though the clones retain proliferative capacity to polyclonal activators (4). This state
has been termed anergy. A hallmark of anergy induction is a defect in IL-2 transcription.
Anergic T cells fail to produce sufficient IL-2 to permit a fully productive immune response
to occur upon restimulation with their relevant antigen (4,5). Antigen-specific non-
responsiveness can be prevented by supplying an exogenous source of IL-2; anergic T cells
reexposed to relevant antigen in the presence of IL-2 acquire the capability of mounting a
productive proliferative response to that antigen (4,5).
