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

作者：Ferrarini Marina; Delfanti Fanny; Gianolini Monica; Rizzi Chiara; Alfano Massimo; Lazzarin Adriano; Biswas Priscilla^*

来源：The Journal of Immunology, 2008, 181(9): 5857-5864.

V gamma 9V delta 2 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 gamma delta lymphocytes differ in their susceptibility to activation-induced apoptosis and proinflammatory phenotype. Activation-induced apoptosis was triggered by anti-CD95 mAbs or by the gamma delta 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 gamma delta cells display constitutive activation of the transcription factor NF-kappa B, which is functionally related to their apoptosis-resistant phenotype. Finally, they spontaneously secreted elevated amounts of the NF-kappa B-regulated chemokines CCL3, CCL4, and CCL5, which likely contributed to down-modulation of the inflammatory CCR5 receptor. Conversely, long-term cultured apoptosis-sensitive gamma delta cells displayed uncleaved caspase-8 and no constitutive NF-kappa 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 gamma delta T lymphocytes, unraveling the crucial role of NF-kappa B in regulating the switch from resistance to apoptosis susceptibility. The Journal of Immunology, 2008, 181: 5857-5864.

• 出版日期2008-11-1