SummaryThe expression of the 70-kD 0 subunit of the interleukin 2 receptor (IL2R) has been examined on peripheral blood lymphocytes (PBL) obtained from patients receiving systemic infusions of 11,2. Using monoclonal antibodies directed against p70, flow cytometric analyses revealed a greater than threefold increase in expression of the IIr2R 0 chain on CD56+ natural killer (NK) cells from post-IL2 therapy PBL relative to pre-therapy cells . The level of p70 expression on the post- or nonspecific mitogenic stimuli, however, results in increased IL-2 and Tac synthesis, followed by a rapid increase in high affinity IL2R expression (1,24) . This activation also leads to increased release of soluble Tac protein from the cells (25). Similar results were noted when purified T cells were cultured directly in IL2 (1,19,24,26) . The latter observation suggests that IL2, when present in sufficient concentrations, directly activates resting Tac -cells through the intermediate affinity p70 0 chain, leading to the synthesis of IL2 and Tac and the formation of Tac/p70 IL-2R complexes . Subsequent autocrine responses to IL-2 would then be mediated by the newly formed high affinity receptors. Consistent with these in vitro observations, increased levels of soluble Tac have been observed in the sera of patients receiving systemic infusions of high-dose 11,2 (27, 28), in the sera of patients experiencing graft rejections (29), and in other forms of in vivo immune activation (30) .

The in vivo administration of repetitive weekly cycles of interleukin-2 (IL-2) to patients with cancer enhances the ability of freshly obtained peripheral blood lymphocytes (PBL) to lyse both the natural-killer(NK)-susceptible K562 and the NK-resistant Daudi targets. Lysis of both targets is significantly augmented by inclusion of IL-2 in the medium during the cytotoxicity assay. This boost is much greater for cells obtained following the in vivo IL-2 therapy than for cells obtained prior to the initiation of therapy or for cells from healthy control donors. In addition to direct lytic activity, the PBL obtained following in vivo IL-2 show a rapid increase in lymphokine-activated killer (LAK) activity with more prolonged in vitro IL-2 exposure, indicating that LAK effectors primed in vivo respond with "secondary-like" kinetics to subsequent IL-2 in vitro. Lymphocytes from healthy control individuals, cultured in IL-2 under conditions attempting to simulate the in vivo IL-2 exposure, function similarly to PBL obtained from patients following IL-2, in that low-level LAK activity was significantly boosted by inclusion of IL-2 during the cytotoxic assay and the cells also responded with secondary-like kinetics to subsequent IL-2 in vitro. The augmentation of the LAK effect was also dependent on the dose of IL-2 added during the 4-h 51Cr-release cytotoxicity assay, with higher doses of IL-2 having a more pronounced effect. While continuous infusion of IL-2 induces a greater cytotoxic potential per milliliter of blood obtained from patients, the peak serum IL-2 levels attained are greater with bolus IL-2 infusions. These pharmacokinetic results, together with the IL-2 dose dependence of LAK activity generated in vivo shown in this report, suggest that a combination of treatment with bolus IL-2 infusions superimposed on continuous IL-2 infusion may transiently expose IL-2 dependent LAK cells, activated in vivo, to higher concentrations of IL-2, facilitating their in vivo cytotoxic potential.

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Culturing of leukemic blood lymphocytes from a patient with acute T- cell lymphoblastic leukemia (T-ALL) with interleukin-2 (IL-2) yielded T- cell line AK-1 with a remarkable cytotoxic specificity. This line mediated strong lysis of tumor target lines expressing major histocompatibility complex (MHC) class I antigens, such as Raji, CEM, and Molt-4 cells, but no killing of K562 and Daudi cells, which are deficient in MHC class I. In contrast, lymphokine-activated killer (LAK) cells from normal donors destroyed all these tumor targets, without MHC restriction. Line AK-1, originating from residual normal T cells present in the leukemic blood, lysed autologous leukemic blasts and peripheral blood lymphocytes (PBL) from many but not all allogeneic individuals but failed to kill autologous remission lymphocytes. Destruction of the autologous leukemic targets by AK-1 could be inhibited by unlabeled competitor target cells that were lysed by AK-1, but not by target cells that were not lysed. This suggests that AK-1 specifically recognized an alien determinant on the autologous ALL cells, crossreactive with allogeneic MHC class I antigens. This reactivity with some degree of tumor specificity may be a leukemic equivalent to responses reported for populations of tumor infiltrating lymphocytes (TIL) seen in some solid tumors.