The ability of human ␥␦ T cells to develop immunologic memory is still a matter of debate. We previously demonstrated the involvement of V␦2 ؊ ␥␦ T lymphocytes in the response of immunosuppressed organ recipients to cytomegalovirus (CMV). Here, we demonstrate their ability to mount an adaptive immune response to CMV in immunocompetent subjects. V␦2 ؊ ␥␦ T-cell peripheral blood numbers, repertoire restriction, and cytotoxicity against CMV-infected fibroblasts were markedly increased in CMV-seropositive, compared with CMV-seronegative, healthy persons. Whereas V␦2 ؊ ␥␦ T cells were found as naive cells in CMV ؊ patients, they virtually all exhibited the cytotoxic effector/ memory phenotype in CMV ؉ patients, which is also observed in transplanted patients challenged with CMV. This longterm complete remodeling of the V␦2 ؊ ␥␦ T-cell population by CMV predicts their ability to exhibit an adaptive anti-CMV immune response. Consistent with this, we observed that the secondary response to CMV was associated with a faster ␥␦ T-cell expansion and a better resolution of infection than the primary response. In conclusion, the increased level of effectormemory V␦2 ؊
IntroductionHuman cytomegalovirus (CMV) is a widespread -herpesvirus that establishes a lifelong viral persistence without detectable symptoms in immunocompetent patients but with life-threatening consequences in immunologically immature or compromised patients. Many studies have been reported that support an important role for adaptive T lymphocytes in the control of CMV infection. [1][2][3][4] In addition, we have demonstrated that the ␥␦ T-cell subpopulation contributes to the anti-CMV immune responses. 5,6 These unconventional T cells are generally considered to be intermediates between innate and adaptive immunity because of their rapid and massive responses to very diverse immune challenges.Compelling data exist that demonstrate the importance of ␥␦ T cells in various microbial infections in humans. They exhibit in vitro reactivity against cells infected by viruses, bacteria, or parasites and are selectively expanded in the peripheral blood of infected patients. [7][8][9][10] The majority of human circulating ␥␦ T cells express a T-cell receptor (TCR) encoded by the V␥9 and V␦2 gene segments. These cells are activated after interaction with nonpeptidic phosphorylated compounds, collectively called phosphoantigens, which are metabolic intermediates of the isoprenoid biosynthetic pathway. 11,12 These phosphoantigens are expressed by a variety of bacteria and parasites and are also present in some tumors. The other ␥␦ T cells are known as V␦2 Ϫ ␥␦ T cells, are largely located in mucosal epithelia and in the spleen, and represent approximately 20% of all circulating ␥␦ T cells. These cells predominantly express a TCR containing the V␦1 region. Their repertoire in the peripheral blood of most healthy adults is restricted, whereas it is polyclonal in the thymus and in cord blood. [13][14][15] This observation suggests that unknown environmental factors encou...