Avidity of influenza‐specific memory CD8+ T‐cell populations decays over time compromising antiviral immunity

Decline of cell‐mediated immunity is often attributed to decaying T‐cell numbers and their distribution in peripheral organs. This study examined the hypothesis that qualitative as well as quantitative changes contribute to the declining efficacy of CD8⁺ T‐cell memory. Using a model of influenza virus infection, where loss of protective CD8⁺ T‐cell immunity was observed 6 months postinfection, we found no decline in antigen‐specific T‐cell numbers or migration to the site of secondary infection. There was, however, a large reduction in antigen‐specific CD8⁺ T‐cell degranulation, cytokine secretion, and polyfunctionality. A profound loss of high‐avidity T cells over time indicated that failure to confer protective immunity resulted from the inferior functional capacity of remaining low avidity cells. These data imply that high‐avidity central memory T cells wane with declining antigen levels, leaving lower avidity T cells with reduced functional capabilities.