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NF-B Modulates Sensitivity to Apoptosis, Proinflammatory and Migratory Potential in Short- versus Long-Term Cultured Human Lymphocytes

Marina Ferrarini^*, Fanny Delfanti^1,, Monica Gianolini, Chiara Rizzi, Massimo Alfano, Adriano Lazzarin^,¶ and Priscilla Biswas^2,

^* Laboratory of Tumor Immunology, Department of Oncology, Laboratory of Clinical Immunology, Department of Infectious Diseases, Unit of Human Virology and AIDS Immunopathogenesis Unit, DIBIT, Department of Infectious Diseases, ^¶ Università Vita-Salute San Raffaele, San Raffaele Scientific Institute, Milan, Italy

V9V2 T lymphocytes are involved in the immune response against hematological malignancies and certain pathogens through the recognition of nonpeptidic Ags expressed by tumors and infected cells. Being equipped with proinflammatory chemokine receptors, they participate to the early phases of inflammation acting as both effector and connector cells between innate and adaptive immunity. We show in this study that after initial TCR triggering short- and long-term cultured lymphocytes differ in their susceptibility to activation-induced apoptosis and proinflammatory phenotype. Activation-induced apoptosis was triggered by anti-CD95 mAbs or by the TCR stimuli isopentenyl pyrophosphate and pamidronate, the latter in the presence of monocytes. In particular, short-term cultured cells are resistant to apoptosis and characterized by expression of anti-apoptotic cellular FLIP molecules and partial spontaneous caspase-8 activation. Linked to this behavior, short-term cells display constitutive activation of the transcription factor NF-B, which is functionally related to their apoptosis-resistant phenotype. Finally, they spontaneously secreted elevated amounts of the NF-B-regulated chemokines CCL3, CCL4, and CCL5, which likely contributed to down-modulation of the inflammatory CCR5 receptor. Conversely, long-term cultured apoptosis-sensitive cells displayed uncleaved caspase-8 and no constitutive NF-B activation; moreover, they secreted CC chemokines only upon TCR triggering coupled to the re-expression of CCR5. The expression of members of the TNF receptor family, including CD30 and TNFRII, also varied according to the time in culture. Altogether our data support a link between resistance to apoptosis and a proinflammatory phenotype in T lymphocytes, unraveling the crucial role of NF-B in regulating the switch from resistance to apoptosis susceptibility.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: Ospedale Maggiore di Lodi, Lodi, Italy.

² Address correspondence and reprint requests to Dr. Priscilla Biswas, San Raffaele Scientific Institute, Department of Infectious Diseases, Via Stamira d’ Ancona 20, 20127 Milan, Italy. E-mail address: biswas.priscilla{at}hsr.it

³ Abbreviations used in this paper: IPP, isopentenyl pyrophosphate; AICD, activation-induced cell death; CD95L, CD95 ligand; cFLIP, cellular FLIP; PI, propidium iodide; PDTC, pyrrolidine dithiocarbamate; Red-DEVD-fmk, sulf-rhodamine-conjugated DEVD-fluoromethyl ketone caspase 3 substrate; SNAP, S-nitrosoacetylpenicillamine; cFLIP_L, cFLIP long; cFLIP_S, cFLIP short.