CD8(+) T cells become nonresponsive (anergic) following activation in the presence of costimulation

CD8(+) T cells stimulated in vitro with anti-TCR mAb and B7-1 or ICAM-1 pro duce IL-2 and clonally expand. Effector function is acquired within 3 days, but proliferation ceases and the cells begin to die by apoptosis, Stimulat ion in vivo with B7-1-expressing allogeneic tumor results in the same seque nce of events with a comparable time course, In both cases, the cells becom e anergic within 3 or 4 days of responding; they can no longer respond by p roducing IL-2 and proliferating, but can still be stimulated to proliferate in response to exogenous IL-2, This activation-induced nonresponsiveness ( AINR) is not simply a consequence of ongoing cell death; cytokines that pro mote survival (IL-7 or IFN-alpha) or proliferation (human IL-2) do not rest ore the ability to produce IL-2 in response to costimulation, Although simi lar to the anergy described for CD4(+) T cell clones, AINR differs in that it results from an initial stimulation with both signal 1 and signal 2, AIN R appears to be an aspect of the normal differentiation of fully stimulated CD8(+) T cells, It is probably important in regulating CTL responses; it l imits the initial T helper-independent response and converts it to a respon se that requires T cell help to be sustained and further expanded. When the initial helper-independent response is not sufficient to clear Ag, and if help is not available, AINR likely results in tolerance to the Ag.