NF-κB modulates sensitivity to apoptosis, proinflammatory and migratory potential in short- versus long-term cultured human γδ lymphocytes

Marina Ferrarini, Fanny Delfanti, Monica Gianolini, Chiara Rizzi, Massimo Alfano, Adriano Lazzarin, Priscilla Biswas

Research output: Contribution to journalArticlepeer-review

Abstract

Vγ9Vδ2 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 γδ lymphocytes differ in their susceptibility to activation-induced apoptosis and proinflammatory phenotype. Activation-induced apoptosis was triggered by anti-CD95 mAbs or by the γδTCR 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 γδ cells display constitutive activation of the transcription factor NF-κB, which is functionally related to their apoptosis-resistant phenotype. Finally, they spontaneously secreted elevated amounts of the NF-κB regulated chemokines CCL3, CCL4, and CCL5, which likely contributed to down-modulation of the inflammatory CCR5 receptor. Conversely, long-term cultured apoptosis-sensitive γδ cells displayed uncleaved caspase-8 and no constitutive NF-κB 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 γδ T lymphocytes, unraveling the crucial role of NF-κB in regulating the switch from resistance to apoptosis susceptibility.

Original languageEnglish
Pages (from-to)5857-5864
Number of pages8
JournalJournal of Immunology
Volume181
Issue number9
Publication statusPublished - Nov 1 2008

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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