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...

Human CD4 T cell recall responses to influenza virus are strongly biased towards Type 1 cytokines, producing IFNγ, IL-2 and TNFα. We have now examined the effector phenotypes of CD4 T cells in more detail, particularly focusing on differences between recent versus long-term, multiply-boosted responses. Peptides spanning the proteome of temporally distinct influenza viruses were distributed into pools enriched for cross-reactivity to different influenza strains, and used to stimulate antigen-specific CD4 T cells representing recent or long-term memory. In the general population, peptides unique to the long-circulating influenza A/New Caledonia/20/99 (H1N1) induced Th1-like responses biased toward the expression of IFNγ+TNFα+ CD4 T cells. In contrast, peptide pools enriched for non-cross-reactive peptides of the pandemic influenza A/California/04/09 (H1N1) induced more IFNγ−IL-2+TNFα+ T cells, similar to the IFNγ−IL-2+ non-polarized, primed precursor T cells (Thpp) that are a predominant response to protein vaccination. These results were confirmed in a second study that compared samples taken before the 2009 pandemic to samples taken one month after PCR-confirmed A/California/04/09 infection. There were striking increases in influenza-specific TNFα+, IFNγ+, and IL-2+ cells in the post-infection samples. Importantly, peptides enriched for non-cross-reactive A/California/04/09 specificities induced a higher proportion of Thpp-like IFNγ−IL-2+TNFα+ CD4 T cells than peptide pools cross-reactive with previous influenza strains, which induced more Th1 (IFNγ+TNFα+) responses. These IFNγ−IL-2+TNFα+ CD4 T cells may be an important target population for vaccination regimens, as these cells are induced upon infection, may have high proliferative potential, and may play a role in providing future effector cells during subsequent infections.

NK cell receptors for MHC class I molecules (MHC-NKR) can be expressed by T cell subsets. The restricted repertoire and phenotypic characteristics of MHC-NKR + T cells indicate that expression of MHC-NKR is acquired upon antigenic challenge and might promote expansion of T cells. Previous studies performed on in vitro generated ab T cell clones concluded that MHC-NKR expression was not a clonal attribute. Here, we examined a massive monoclonal expansion of a non-leukemic cd T cell population found in the peripheral blood of a lung-transplanted patient who suffered from a cytomegalovirus infection. Despite their monoclonality, these T cells displayed a heterogeneous and stable in vivo Ig-and lectin-like MHC-NKR phenotype. Twenty percent of the cells displayed a CD94 + NKG2A + phenotype, and 10% were labeled with an anti-CD158b1/b2/j monoclonal antibody. A CD158b/j + cd T cell clone derived in vitro from patient's peripheral blood lymphocytes was shown to express the activating form CD158j (KIR2DS2), which once cross-linked stimulated the clone cytolytic function and costimulated the TCR-induced production of cytokines, independently of the killer-activating receptor-associated protein (KARAP). In conclusion, heterogeneity of MHC-NKR expression confers a functional intraclonal diversity that may participate to induction of specific cd T cell effector functions or proliferation upon pathogen challenge.