Protective CD8 T cell memory is impaired during chronic CD70-driven costimulation.

Chronic infection results in continuous formation and exhaustion of effector CD8 T cells and in failure of memory CD8 T cell development. Expression of CD70 and other molecules that provide costimulation to T cells is maintained during chronic infection. To analyze the impact of constitutive CD70-driven costimulation, we generated transgenic mice expressing CD70 specifically on T cells. We show that CD70 promoted accumulation of CD8 T cells with characteristics strikingly similar to exhausted effector CD8 T cells found during chronic infection. CD70 on T cells provided costimulation that enhanced primary CD8 T cell responses against influenza. In contrast, memory CD8 T cell maintenance and protection against secondary challenge with influenza was impaired. Interestingly, we found no effect on the formation of either effector or memory CD4 T cells. We conclude that constitutive expression of CD70 is sufficient to deregulate the CD8 T cell differentiation pathway of acute infection reminiscent of events in chronic infection.