Activation of nuclear factor of activated T cells by human T-lymphotropic virus type 1 accessory protein p12I

Björn Albrecht, Celine D. D'Souza, Wei Ding, Susheela Tridandapani, K. Mark Coggeshall, Michael Dale Lairmore

Research output: Contribution to journalArticle

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Abstract

Human T-lymphotropic virus type 1 (HTLV-1) is the agent of an aggressive malignancy of CD4+ T lymphocytes, called adult T-cell lymphoma/leukemia, and is associated with numerous immune-mediated diseases. To establish infection, HTLV-1 must activate targeted T cells during early stages of infection. We recently demonstrated that the HTLV-1 accessory protein p12I is critical for persistent infection in vivo and for viral infectivity in quiescent primary lymphocytes, suggesting a role for p12I in lymphocyte activation. To test whether p12I modulates signaling pathways required for T-lymphocyte activation, we examined AP-1-, NF-κB-, and nuclear factor of activated T cells (NFAT)-driven reporter gene activity in p12I-expressing Jurkat T cells compared to vector-transfected control cells. HTLV-1 p12I specifically induced NFAT-mediated transcription approximately 20-fold in synergy with the Ras/mitogen-activated protein kinase pathway, but did not influence AP-1- or NF-κB-dependent gene expression. Inhibition of calcium-dependent signals by cyclosporin A, BAPTA-AM [glycine, N,N′-1,2-ethanediylbis(oxy-2,1-phenylene)- bis-N-2-(acetyloxy)methoxy-2-oxoethyl]-[bis (acetyloxy)methyl ester], and a dominant negative mutant of NFAT2 abolished the p12I-mediated activation of NFAT-dependent transcription. In contrast, inhibition of phospholipase C-γ and LAT (linker for activation of T cells) did not affect p12I-induced NFAT activity. Importantly, p12I functionally substituted for thapsigargin, which selectively depletes intracellular calcium stores. Our data are the first to demonstrate a role for HTLV-1 p12I in calcium-dependent activation of NFAT-mediated transcription in lymphoid cells. We propose a novel mechanism by which HTLV-1, a virus associated with lymphoproliferative disease, dysregulates common T-cell activation pathways critical for the virus to establish persistent infection.

Original languageEnglish (US)
Pages (from-to)3493-3501
Number of pages9
JournalJournal of Virology
Volume76
Issue number7
DOIs
StatePublished - 2002
Externally publishedYes

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NFATC Transcription Factors
Human T-lymphotropic virus 1
T-lymphocytes
T-Lymphocytes
viruses
proteins
Transcription Factor AP-1
Lymphocyte Activation
Infection
Calcium
Lymphocytes
Viruses
Adult T Cell Leukemia Lymphoma
Critical Pathways
Jurkat Cells
Thapsigargin
transcription (genetics)
Immune System Diseases
Type C Phospholipases
lymphocyte proliferation

ASJC Scopus subject areas

  • Immunology

Cite this

Activation of nuclear factor of activated T cells by human T-lymphotropic virus type 1 accessory protein p12I. / Albrecht, Björn; D'Souza, Celine D.; Ding, Wei; Tridandapani, Susheela; Coggeshall, K. Mark; Lairmore, Michael Dale.

In: Journal of Virology, Vol. 76, No. 7, 2002, p. 3493-3501.

Research output: Contribution to journalArticle

Albrecht, Björn ; D'Souza, Celine D. ; Ding, Wei ; Tridandapani, Susheela ; Coggeshall, K. Mark ; Lairmore, Michael Dale. / Activation of nuclear factor of activated T cells by human T-lymphotropic virus type 1 accessory protein p12I. In: Journal of Virology. 2002 ; Vol. 76, No. 7. pp. 3493-3501.
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AU - Lairmore, Michael Dale

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