Cytokine deprivation from activated T cells leads to apoptosis associated with down-regulation of the bcl-2 gene product. It is not clear, however, how cytokines other than interleukin-2 (IL-2) may affect this process and regulate the involvement of other apoptosis-modulating genes. We show that a group of cytokines including IL-2 (IL-2R gamma), prevent the apoptosis of IL-2-deprived activated T cells. This rescue involves the induction of the anti-apoptosis genes bcl-2 and bcl-xL), but causes little change in expression of bax and bcl-xS, which promote apoptosis. Furthermore, the prevention of apoptosis and induction of proliferation by the common gamma chain cytokines can be dissociated. Thus, when proliferation is blocked, the common gamma chain cytokines still induce up-regulation of bcl-2 relative to bax and retard apoptosis. These cytokines can thus regulate the persistence or removal of effector T cells by coordinating the balance between genes which promote and those which inhibit apoptosis, events which are probably mediated at least in part by signals through the common gamma chain. These data also implicate inappropriate T cell apoptosis resulting from a dysfunctional common gamma-chain as part of the pathophysiological defect in patients with X-linked severe-combined immunodeficiency (SCID).

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SummaryThe bcl-2 gene product has been shown to prevent apoptotic cell death. We have now investigated the bcl-2 protein expression by resting and activated mature T cell populations. Freshly isolated CD45RO + T cells within CD4 + and CD8 + subsets expressed significantly less bcl-2 than CD45RO-(CD45RA +) T cells ~ <0.001). When CD45RA + T cells within both CD4 ~ and CD8 + subsets were activated in vitro, the transition to CD45RO phenotype was associated with a decrease in bcl-2 expression. Patients with acute viral infections such as infectious mononucleosis caused by Epstein-Barr virus infections or chickenpox, resulting from variceUa zoster virus infection, had circulating populations of activated CD45RO + T cells which also showed low bcl-2 expression. In these patients, a significant correlation was seen between low bcl-2 expression by activated T cells and their apoptosis in culture (r = 0.94, p <0.001). These results suggest that the primary activation of T cells leads to the expansion of a population that is destined to perish unless rescued by some extrinsic event. Thus the suicide of CD45RO + T cells could be prevented by the addition ofinterleukin 2 to the culture medium which resulted in a concomitant increase in the bcl-2 expression of these cells. Alternatively, apoptosis was also prevented by coculturing the activated T lymphocytes with fibroblasts, which maintained the viability of lymphoid cells in a restinglike state but with low bcl-2 expression. The paradox that the CD45RO + population contains the primed/memory T cell pool yet expresses low bcl-2 and is susceptible to apoptosis can be reconciled by the observations that maintenance of T cell memory may be dependent on the continuous restimulation of T cells, which increases their bcl-2 expression. Furthermore, the propensity of CD45RO + T cells to extravasate may facilitate encounter with fibroblast-like cells in tissue stroma and thus be an important additional factor which promotes the survival of selected primed/memory T cells in vivo.

In healthy blood donors, serological positivity for human cytomegalovirus (HCMV) is associated with an increased proportion of NK cells bearing the CD94/NKG2C NK cell receptor (NKR). The expression of the activating CD94/NKG2C NKR and of the inhibitory CD94/NKG2A NKR was studied in a cohort of 45 aviremic human immunodeficiency virus type 1 (HIV-1)-positive patients receiving highly active antiretroviral therapy. The proportions of NKG2C+ NK cells were significantly increased in HIV-1-positive patients (mean +/- SD, 25.9% +/- 23.0%), compared with those in 31 healthy individuals (mean +/- SD, 16.1% +/- 20.7%). Yet, the association vanished when HCMV serological status was considered in a multivariate regression model. These results support the conclusion that changes in the NKR repertoire in HIV1-positive patients are related to a concomitant HCMV infection.

Dendritic cells (DCs) are specialized antigen-presenting cells. However, DCs exposed to human immunodeficiency virus type 1 (HIV-1) are also able to transmit a vigorous cytopathic infection to CD4؉ T cells, a process that has been frequently related to the ability of DC-SIGN to bind HIV-1 envelope glycoproteins. The maturation of DCs can increase the efficiency of HIV-1 transmission through trans infection. We aimed to comparatively study the effect of maturation in monocyte-derived DCs (MDDCs) and bloodderived myeloid DCs during the HIV-1 capture process. In vitro capture and transmission of envelopepseudotyped HIV-1 and its homologous replication-competent virus to susceptible target cells were assessed by p24 gag detection, luciferase activity, and both confocal and electron microscopy. Maturation of MDDCs or myeloid DCs enhanced the active capture of HIV-1 in a DC-SIGN-and viral envelope glycoprotein-independent manner, increasing the life span of trapped virus. Moreover, higher viral transmission of mature DCs to CD4 ؉ T cells was highly dependent on active viral capture, a process mediated through cholesterol-enriched domains. Mature DCs concentrated captured virus in a single large vesicle staining for CD81 and CD63 tetraspanins, while immature DCs lacked these structures, suggesting different intracellular trafficking processes. These observations help to explain the greater ability of mature DCs to transfer HIV-1 to T lymphocytes, a process that can potentially contribute to the viral dissemination at lymph nodes in vivo, where viral replication takes place and there is a continuous interaction between susceptible T cells and mature DCs.

Summary The interferon (IFN)‐γ component of the immune response plays an essential role in combating infectious and non‐infectious diseases. Induction of IFN‐γ secretion by human T and natural killer (NK) cells through synergistic costimulation with interleukin (IL)‐12 and IL‐18 in the adaptive immune responses against pathogens is well established, but induction of similar activity in macrophages is still controversial, with doubts largely focusing on contamination of macrophages with NK or T cells in the relevant experiments. The possible contribution of macrophages to the IFN response is, however, an important factor relevant to the pathogenesis of many diseases. To resolve this issue, we analysed the production of IFN‐γ at the single‐cell level by immunohistochemistry and by enzyme‐linked immunosorbent spot (ELISPOT) analysis and unequivocally demonstrated that human macrophages derived from monocytes in vitro through stimulation with a combination of IL‐12 and IL‐18 or with macrophage colony‐stimulating factor (M‐CSF) were able to produce IFN‐γ when further stimulated with a combination of IL‐12 and IL‐18. In addition, naturally activated alveolar macrophages immediately secreted IFN‐γ upon treatment with IL‐12 and IL‐18. Therefore, human macrophages in addition to lymphoid cells contribute to the IFN‐γ response, providing another link between the innate and acquired immune responses.

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