DLG1 alternative splice variants: molecular conduits specifying proximal TCR signals to distinct CTL functional responses

Abstract CD8+ cytotoxic T lymphocytes (CTLs) are a critical component of the adaptive immune system because they mediate contact-dependent cytolysis and produce proinflammatory cytokines. Although both of these CTL activities require T cell receptor (TCR) activation these functions are not always coordinately invoked, suggesting that signaling pathways downstream of the TCR can be selectively activated to guide specific functional outcomes. Here we investigated the role of Discs large homolog 1 (DLG1) alternative splice variants, DLG1 i1A-i1B and DLG1 i1B, in coupling proximal TCR signals to select downstream pathways to specify cytotoxicity and proinflammatory cytokine transcription in CD8+ T cells. We found that DLG1 i1A-i1B, but not DLG1 i1B selectively directs TCR-induced p38/NFAT-dependent proinflammatory cytokine production by binding Lck, promoting alternative p38 activation and downstream NFAT mediated upregultion of IFNγ and TNFα gene expression. Conversely, DLG1 i1A-i1B mediated alternative p38 activation had no effect on actin polymerization, granzyme B gene expression, granzyme B release, or degranulation. Rather, either DLG1 variant expressed in CD8+ T cells promoted antigen-induced degranulation, suggesting that both DLG1 variants have p38-independent activity guiding granule-dependent cytotoxicity. Thus CD8+ T cells contain two distinct DLG1 scaffolds that act as molecular conduits for proximal TCR signals to allow differential CTL functional responses.