T cell antigen receptor zeta chain down-regulation and impaired in vitro T cell function have been described in cancer and autoimmune and infectious diseases. However, the immunological basis for this phenomenon is unknown. Sustained exposure to antigen and chronic systemic inflammation, factors shared by the various pathologies, might account for this phenomenon. We developed an in vivo experimental system that mimics these conditions and show that sustained exposure of mice to bacterial antigens was sufficient to induce T cell antigen receptor zeta chain down-regulation and impair T cell function, provided an interferon-gamma-dependent T helper type 1 immune response developed. This indicates zeta chain down-regulation could be a physiological response that attenuates an exacerbated immune response. However, it can act as a 'double-edged sword', impairing immune responses to chronic diseases.