Deficient expression of p56(lck) in Th2 cells leads to partial TCR signaling and a dysregulation in lymphokine mRNA levels.

Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.

Deficient expression of p56(lck) in Th2 cells leads to partial TCR signaling and a dysregulation in lymphokine mRNA levels.

J Immunol. 1996 Dec 1;157(11):4751-61. Unique Identifier : AIDSLINE MED/97098699
al-Ramadi BK; Nakamura T; Leitenberg D; Bothwell AL; Section of Immunobiology, Yale University School of Medicine, New; Haven, CT 06520, USA.

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, p56(lck) (Lck) and p59(fyn) (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-zeta and ZAP-70, defective Ca2+ mobilization, and a approximately 90% reduction in proliferative 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.

Keywords: src-Family Kinases/DEFICIENCY/*GENETICS Animal Base Sequence Calcium/METABOLISM Cell Line DNA Primers/GENETICS Gene Expression Immune Tolerance Interleukin-10/GENETICS Interleukin-4/GENETICS Interleukin-5/GENETICS Lymphocyte Transformation Lymphokines/*GENETICS Membrane Proteins/*METABOLISM Mice Phosphorylation Protein-Tyrosine Kinase/METABOLISM Receptors, Antigen, T-Cell/*METABOLISM RNA, Messenger/*GENETICS/*METABOLISM Signal Transduction Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. Th2 Cells/*ENZYMOLOGY/*IMMUNOLOGY/METABOLISM Transfection JOURNAL ARTICLE
970228
M9721855

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