Abstract
Functionally diverse CD8+ T cells develop in response to antigenic stimulation with differing capacities to couple TCR engagement to downstream signals and functions. However, mechanisms of diversifying TCR signaling are largely uncharacterized. Here we identified two alternative splice variants of scaffold protein Dlg1, Dlg1AB and Dlg1B, that diversify signaling to regulate p38 –dependent and –independent effector functions in CD8+ T cells. Dlg1AB, but not Dlg1B associated with Lck, coupling TCR stimulation to p38 activation and proinflammatory cytokine production. Conversely, both Dlg1AB and Dlg1B mediated p38-independent degranulation. Degranulation depended on a Dlg1 fragment containing an intact Dlg1SH3-domain and required the SH3-ligand WASp. Further, Dlg1 controlled WASp activation by promoting TCR-triggered conformational opening of WASp. Collectively, our data support a model where Dlg1 regulates p38-dependent proinflammatory cytokine production and p38-independent cytotoxic granule release through the utilization of alternative splice variants, providing a mechanism whereby TCR engagement couples downstream signals to unique effector functions in CD8+ T cells.
Highlights
CD8+ cytotoxic T lymphocytes (CTLs) are critical components of the adaptive immune response due to their ability to produce proinflammatory cytokines and induce target cell killing through lytic factor degranulation
To investigate if alternative splicing of dlg1 occurs in T cells we developed PCR primers that flanked the i1A/i1B or i3/i2/i5/i4 splicing regions (Fig 1A) and amplified cDNA from: freshly isolated CD8+ T cells, in vitro differentiated CTL, Th1, Th2 and T cell hybridomas, and DNA sequenced the PCR products
In response to influenza, the development of lung infiltrating CTLs lacking proinflammatory cytokine responsiveness is correlated with better clinical course [1, 39]
Summary
CD8+ cytotoxic T lymphocytes (CTLs) are critical components of the adaptive immune response due to their ability to produce proinflammatory cytokines and induce target cell killing through lytic factor degranulation. These distinct CTL functions are often required to efficiently clear intracellular pathogens, they are not always coordinately invoked [1]. CD8+ CTLs can selectively degranulate but not produce proinflammatory.
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