Deficient Expression of p56lck in Th2 Cells Leads to Partial TCR Signaling and a Dysregulation in Lymphokine mRNA Levels

Basel K. Al-Ramadi, Tetsuo Nakamura, David Leitenberg, Alfred L.M. Bothwell

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

Activation of T lymphocytes through their TCR is regulated by a delicate balance of phosphorylation and dephosphorylation of protein substrates by protein tyrosine kinases (PTKs) and phosphotyrosyl phosphatases, respectively. One of the earliest steps in the activation pathway is thought to involve the Src family PTKs, p56lck (Lck) and p59fyn (Fyn); however, the precise contribution of each PTK in TCR-mediated signaling remains incompletely understood. To study the role of Lck in mature T cells, antisense RNA was used to inhibit its expression in a nontransformed Th2 clone. In this report, we demonstrate that specific inhibition of Lck expression in Th2 cells, in the presence of normal levels of functional Fyn PTK, has profound consequences on multiple events following TCR stimulation, including an altered pattern of tyrosine-phosphorylated substrates, defective phosphorylation of TCR-ζ and ZAP-70, defective Ca2+ mobilization, and a ∼90% reduction in proliferate responses to antigenic and mitogenic stimuli. In contrast, Lck-deficient cells expressed constitutively elevated levels of lymphokine mRNA, including IL-4, IL-5, and IL-10, and were capable of secreting IL-4 upon activation through the TCR. These results demonstrate a dissociation in functional responses in Lck-deficient Th2 cells and suggest a role for Lck in the induction of a state of T cell unresponsiveness.

Original languageEnglish
Pages (from-to)4751-4761
Number of pages11
JournalJournal of Immunology
Volume157
Issue number11
Publication statusPublished - Dec 1 1996
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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