Characterization of a subset of antigen-specific human central memory CD4+ T lymphocytes producing effector cytokines

CCR7(+) central memory (T-CM) CD4(+) T cells play a central role in long-term immunological memory. Recent reports indicate that a proportion of CD4(+) T-CM is able to produce effector cytokines. The phenotype and the role of this subset remain unknown. We characterized cytokine-producing human CD4(+) T-CM specific for cleared protein and persistent viral Ag. Our results demonstrate that the type of Ag stimulation is a major determinant of CD4(+) T-CM differentiation. CMV-specific T-CM were significantly more differentiated than protein Ag-specific T-CM and included higher proportions of IFN-gamma-producing cells. The expression of killer cell lectin-like receptor G1 (KLRG1) by protein Ag- and CMV-specific T-CM was associated with increased production of effector cytokines. KLRG1(+) T-CM expressed high levels of CD127, suggesting that they can survive long term under the influence of IL-7. The induction of KLRG1(+) T-CM may therefore represent an important target of vaccination against pathogens controlled by cellular immune responses.