PAG/Cbp suppression reveals a contribution of CTLA-4 to setting the activation threshold in T cells
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RESEARCH
Open Access
PAG/Cbp suppression reveals a contribution of CTLA-4 to setting the activation threshold in T cells Michal Smida1,2, Clemens Cammann1, Slavyana Gurbiel1, Nadja Kerstin1, Holger Lingel3, Sabine Lindquist4,5, Luca Simeoni1, Monika C Brunner-Weinzierl3, Miloslav Suchanek6, Burkhart Schraven1,7 and Jonathan A Lindquist1,8*
Abstract Background: PAG/Cbp represents a ubiquitous mechanism for regulating Src family kinases by recruiting Csk to the plasma membrane, thereby controlling cellular activation. Since Src kinases are known oncogenes, we used RNA interference in primary human T cells to test whether the loss of PAG resulted in lymphocyte transformation. Results: PAG-depletion enhanced Src kinase activity and augmented proximal T-cell receptor signaling; exactly the phenotype expected for loss of this negative regulator. Surprisingly, rather than becoming hyper-proliferative, PAG-suppressed T cells became unresponsive. This was mediated by a Fyn-dependent hyper-phosphorylation of the inhibitory receptor CTLA-4, which recruited the protein tyrosine phosphatase Shp-1 to lipid rafts. Co-suppression of CTLA-4 abrogates this inhibition and restores proliferation to T cells. Conclusion: We have identified a fail-safe mechanism as well as a novel contribution of CTLA-4 to setting the activation threshold in T cells. Keywords: Human, T cells, Protein kinases, Cell activation, Tolerance
Background T cells orchestrate the adaptive immune response. However, to fulfill this function they must first be activated by specific antigenic peptides presented by MHC molecules. How T cells are able to distinguish self antigens from foreign is an important question, as inappropriate activation may lead to autoimmunity. It was long held that self-reactive T cells are deleted in the thymus. However, the presence of mechanisms that induce peripheral tolerance, as well as the observation that both peripheral conventional and regulatory T cells can be self-reactive has challenged this view. Although it is now accepted that autoreactive T cells escape the thymus [1], it remains unclear how the threshold for activation is set to ensure that these potentially destructive * Correspondence: [email protected] 1 Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Strasse 44, Magdeburg 39120, Germany 8 Current address: Department of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, Magdeburg 39120, Germany Full list of author information is available at the end of the article
cells remain quiescent. The activation threshold for T cells appears to be determined by a number of TCR-induced proximal feedback loops [2]. One such loop involves the tight control over the activation of Src family kinases, Lck and Fyn [3], by the phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), also known as the Csk binding protein (Cbp); a transmembrane adaptor protein [hereafter referred to as PAG]. The primar
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