Activation-induced non-responsiveness (anergy) limits CD8 T cell responses to tumors

Abstract

Naïve CD8 T cells respond to signals provided by Ag, costimulation and cytokines by proliferating and differentiating to develop effector functions. Following initial clonal expansion, however, the cells develop activation-induced non-responsiveness (AINR), a form of anergy characterized by an inability to produce IL-2. Cells in the AINR state can carry out effector functions (cytolysis, IFN-gamma production) but cannot continue to proliferate and expand in the face of persisting Ag. AINR limits the ability of activated CTL to control tumor growth but can be reversed by IL-2, provided either therapeutically or by activated CD4 T helper cells, to allow continued expansion.

Figure 1. Comparison of responses in post-stimulation CD4 and CD8 T cells

T cells were either naïve (Day 0) or stimulated with anti-TCR mAb and B7-1 in vitro for the indicated times. Cells were then washed, stimulated with the indicated stimulus, and their IL-2 production and survival assessed. In addition, CD8 T cells were harvested on day 3, cultured for 2 additional days in IL-2 to reverse AINR, and restimulated (‘AINR Reversed’). A + indicates that response occurred, a – indicates that it did not. nd, not determined. (Adapted from ref. 50).

Figure 2. Model for IL-2 dependent CD4 T cell help at a peripheral site to reverse AINR in effector CD8 T cells

See text for discussion.

Figure 3. Time course for the response of CD8 T cells to tumor growing in the peritoneal cavity, and the effects of IL-2 administration at varying times

Mice received OT-I CD8 T cells by adoptive transfer, and were then challenged by i.p. injection of E.G7 tumor. Left panel: The numbers of OT-I T cells and E.G7 tumor cells in the peritoneal cavity, and the OT-I T cells in the spleen during the course of tumor growth. Lettered black bars indicate the times of treatment with low dose IL-2. Right panel: The tumor load in groups of mice treated with IL-2 at the times indicated in the left panel, expressed as a percent of the tumor burden in untreated control mice. (Adapted from ref. 64).