Cytotoxic T-lymphocyte (CTL) responses to human immunodeficiency virus arise early after infection, but ultimately fail to prevent progression to AIDS. Human immunodeficiency virus may evade the CTL response by accumulating amino-acid replacements within CTL epitopes. We studied 10 CTL epitopes during the course of simian immunodeficiency virus disease progression in three related macaques. All 10 of these CTL epitopes accumulated amino-acid replacements and showed evidence of positive selection by the time the macaques died. Many of the amino-acid replacements in these epitopes reduced or eliminated major histocompatibility complex class I binding and/or CTL recognition. These findings strongly support the CTL 'escape' hypothesis.

The mechanisms by which HIV-1 infection kills T lymphocytes are not clearly established. Apoptosis is an internally programmed cell death pathway that may regulate both T cell development and senescence, and that is characterized by cleavage of DNA at internucleosomal regions. The present experiments show that acute HIV-1 infection of MT2 lymphoblasts and activated normal peripheral blood mononuclear cells induces apoptosis.

IntroductionNatural killer (NK) cells contribute to innate immune responses against virally infected and neoplastic cells. 1 NK cells usually recognize and attack tumor cells that lack major histocompatibility complex (MHC) class I. 2 Our previous studies in murine tumor models clearly demonstrated that gamma delta (␥␦) T lymphocytes play an important role in the regulation of antitumor NK-cell function. 3 Specifically, we have shown that ␥␦ T lymphocytes are required for the antitumor activity of NK cells in vivo. More recently, we have demonstrated that culturing human peripheral blood mononuclear cells (PBMCs) with agents that activate ␥␦ T lymphocytes induce NK cell-mediated cytotoxicity against tumors that normally resist NK killing. 4 These findings are concordant with other studies that show that ␥␦ T lymphocytes regulate the early phase of NK cell-mediated antibacterial responses in mice. 5 Taken in concert these data strongly suggest that ␥␦ T lymphocytes are important in the regulation of NK-cell functions.␥␦ T cells are characterized by the expression of a T-cell receptor (TCR) consisting of both gamma and delta chains, 6 and account for 1% to 10% of CD3 ϩ cells in the peripheral blood of healthy adults. 7 Approximately 70% of ␥␦ T lymphocytes express the V␥2V␦2 TCR and can be expanded and activated by phosphoantigens such as the cholesterol biosynthesis intermediate, isopentenylpyrophosphate (IPP), or synthetic bisphosphonates (eg, pamidronate disodium and zoledronic acid). [8][9][10] Upon stimulation, ␥␦ T lymphocytes acquire the capacity to destroy solid tumors of diverse origins such as squamous cell carcinoma of the head and neck (SCCHN), melanoma, colon cancer, and breast carcinoma, 4,[11][12][13] suggesting that ␥␦ T lymphocytes are important antitumor effector cells. The validity of this antitumor function is further supported by mouse models demonstrating that mice deficient in ␥␦ T cells have increased sensitivity to the development of methylcholanthrene (MCA)-induced tumors. 14 In addition, a recent pilot clinical study showed that ␥␦ T lymphocyte adoptive therapy for patients with advanced renal cell carcinoma was well tolerated and induced antitumor immune responses. 15 The antitumor effects of ␥␦ T lymphocytes are recognized to result from both direct killing of tumor targets and trans-activation of adaptive immune responses. For example, recent data demonstrate that activated ␥␦ T lymphocytes cause the maturation of dendritic cells that promote development of acquired immunity. 16 In addition, ␥␦ T cells are known to cross-present tumor antigens (Ags) to CD8 ϩ cytolytic T lymphocytes. 17,18 Despite their wellcharacterized role in mediating adaptive immune responses, the mechanisms by which ␥␦ T cells regulate cells of the innate immune system, such as NK cells, are unclear.In this report we demonstrate that ␥␦ T lymphocytes provide a costimulatory function for NK cells stimulated with suboptimal doses of immobilized human immuglobulin G1 (hIgG1). Costimulated NK cells display up-regulat...

Purpose: The expression of CD56, a natural killer cell^associated molecule, on ah T lymphocytes correlates with their increased antitumor effector function. CD56 is also expressed on a subset of gy T cells. However, antitumor effector functions of CD56 + gy T cells are poorly characterized. Experimental Design: To investigate the potential effector role of CD56 + gy T cells in tumor killing, we used isopentenyl pyrophosphate and interleukin-2^expanded gyTcells from peripheral blood mononuclear cells of healthy donors. Results: Thirty to 70% of expanded gy T cells express CD56 on their surface. Interestingly, although both CD56+ and CD56 -gy Tcells express comparable levels of receptors involved in the regulation of gy T-cell cytotoxicity (e.g., NKG2D and CD94), only CD56 + gy T lymphocytes are capable of killing squamous cell carcinoma and other solid tumor cell lines. This effect is likely mediated by the enhanced release of cytolytic granules because CD56 + gy T lymphocytes expressed higher levels of CD107a compared with CD56 -controls following exposure to tumor cell lines. Lysis of tumor cell lines is blocked by concanamycin A and a combination of anti-gy T-cell receptor + anti-NKG2D monoclonal antibody, suggesting that the lytic activity of CD56 + gy T cells involves the perforin-granzyme pathway and is mainly gy T-cell receptor/NKG2D dependent. Importantly, CD56-expressing gy T lymphocytes are resistant to Fas ligand and chemically induced apoptosis. Conclusions: Our data indicate that CD56 + gy Tcells are potent antitumor effectors capable of killing squamous cell carcinoma and may play an important therapeutic role in patients with head and neck cancer and other malignancies.