Repetitive antigen stimulations disarm specific human T lymphocytes

In mouse models of chronic viral infection and cancer, T cells lose the ability to proliferate and exert effector functions, and are considered to be exhausted. It is difficult to establish whether these cells are dysfunctional because of antigen persistence, inflammatory conditions or a suppressive microenvironment. In humans, the corresponding T cells can only be tested ex vivo, which provides a momentary snapshot of their function only. To examine whether repetitive rounds of antigen exposure can cause human T cell dysfunction, we subjected human antigen-specific CD8+ T cells to repeated stimulations with either melanoma cells or antigenpresenting mature dendritic cells. Human T cells lost cytokine production and lytic activity while retaining proliferation. Antigen removal failed to restore function. Surface expression of inhibitory receptors cannot explain the dysfunction. We concluded that repetitive rounds of antigen stimulations are sufficient to render human CD8+ T cell dysfunctional. Consequently, therapeutical strategies should not only target the suppressive environment but also the mechanisms underlying this dysfunction.