Positive and negative regulation of T cell responses by Lck-dependent signaling pathways
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AbstractAppropriate T cell signaling is essential for the function of the human immune system. T cells regulate and direct the body’s response to foreign pathogens such as virus and bacteria, or threats from within in the form of cancerous cells. Aberrant T cell activation may lead to either immune deficiency or autoimmune diseases such as diabetes or rheumatoid arthritis.
The Src-family tyrosine kinase Lck is of vital importance in the intracellular T cell signaling machinery. We have targeted Lck using siRNA-mediated RNA interference and investigated signaling properties in T cells with Lck knockdown (Lck-kd). As expected, proximal signaling was reduced in Lck-kd cells, as determined by overall tyrosine phosphorylation, CD3-zeta phosphorylation and Ca2+ mobilization. Despite this, NFAT-AP-1 activation and IL-2 secretion was increased. This paradoxical result required further investigation. We found that Grb2-SOS1 was recruited to hypophosphorylated CD3-zeta in Lck-kd cells, leading to sustained Ras-Raf-1-ERK1/2 activation. Furthermore, endocytosed TCR/CD3-containing vesicles were not targeted to lysosomes, and as a result, CD3-zeta levels remained elevated for several hours after stimulation. Prolonged survival of internalized TCR/CD3-complexes may lead to sustained signaling through the Grb2-SOS1-Ras-ERK pathway, and if allowed to operate in the absence of negative feedback normally imposed by Lck, this mechanism my result in hyperresponsive signaling. Our data demonstrate a crucial role for Lck as both a positive and negative regulator of T cell activation. Alternative or aberrant mechanisms of T cell activation may be of importance in the development of immune system pathologies, such as autoimmune diseases.
2. List of publications included
Paper I Methi T, Ngai J, Mahic M, Amarzguioui M, Vang T and Taskén K. Short-interfering RNA-mediated Lck knockdown results in augmented downstream T cell responses.Journal of Immunology 2005, 175:7398-7406. Artikkel
Paper II Methi T, Ngai J, Vang T, Torgersen KM and Taskén K. Hypophosphorylated TCR/CD3-zeta signals through a Grb2-SOS1-Ras pathway in Lck knockdown cells.European Journal of Immunology 2007, 37:2539-2548. Artikkel
Paper III Methi T, Torunn Berge, Torgersen KM and Taskén K. Reduced Cbl phosphorylation and CD3-zeta degradation in T cells with low Lck levels. Manuscript submitted.
Paper IV Ngai J, Methi T, Andressen KW, Levy FO, Torgersen KM, Vang T, Wettschureck N and Taskén K. Gaq regulates TCR-mediated immune response in T cells through an Lck-dependent pathwayManuscript submitted.