Differential implication of protein kinase C isoforms in cytotoxic T lymphocyte degranulation and TCR-induced Fas ligand expression

Pardo, Julián; Buferne, Michel; Martínez‐Lorenzo, María‐José; Naval, Javier; Schmitt‐Verhulst, Anne‐Marie; Boyer, Catherine; Anel, Alberto

doi:10.1093/intimm/dxg141

Cited by 29 publications

(36 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because CTL also can kill via FasL-mediated crosslinking of Fas on other cells (28,30), we assessed the FasL expression on cells from WT and KO mice. Preimmune CD8 + T cells from KO mice expressed modestly higher FasL levels on the cell surface than did cells from WT mice, but their intracellular FasL expression was more than 40-fold higher (Fig.…”

Section: Resultsmentioning

confidence: 99%

Duality of the murine CD8 compartment

Genolet

Leignadier

Østerås

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

CD8αβ plays crucial roles in the thymic selection, differentiation, and activation of some, but not all, CD8 + T cells, whereas CD8αα does not. To investigate these roles, we produced mice that expressed transgene P14 T-cell receptor β (TCRβ) chain and CD8β or did not (WT and KO mice, respectively). The primary CD8 + T-cell response to acute lymphocytic choriomeningitis virus (LCMV) infection was predominantly D b /GP33 specific and CD8 independent in KO mice and was mostly CD8 dependent in WT mice. Cytotoxic T lymphocytes (CTL) from KO mice failed to mobilize intracellular Ca 2+ and to kill via perforin/granzyme. Their strong Fas/FasL-mediated cytotoxicity and IFN-γ response were signaled via a Ca 2+ -independent, PI3K-dependent pathway. This was also true for 15-20% of CD8-independent CTL found in WT mice. Conversely, the perforin/granzyme-mediated killing and IFN-γ response of CD8-dependent CTL were signaled via a Ca 2+ , p56 lck , and nuclear factor of activated T cells-dependent pathway. Deep sequencing of millions of TCRα chain transcripts revealed that the TCR repertoires of preimmune CD8 + T cells were highly diverse, but those of LCMV D b /GP33-specific CTL, especially from KO mice, were narrow. The immune repertoires exhibited biased use of Vα segments that encoded different complementary-determining region 1α (CDR1α) and CDR2α sequences. We suggest that TCR from WT CD8-independent T cells may engage MHC-peptide complexes in a manner unfavorable for efficient CD8 engagement and Ca 2+ signaling but permissive for Ca 2+

show abstract

Section: Resultsmentioning

confidence: 99%

Duality of the murine CD8 compartment

Genolet

Leignadier

Østerås

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Degranulation, but not all CTLmediated killing, is inhibited with extracellular Ca 2ϩ depletion (10,24). Additionally, perforin-dependent cytotoxicity is classical protein kinase C-dependent, whereas TCR-CD3-induced FasL expression is not (25). In another study, a CTL clone that failed to mobilize intracellular Ca 2ϩ after TCR engagement was unable to kill via the degranulation mechanism of killing, yet was still able to kill via the FasL/Fas mechanism in an Agspecific manner (26).…”

Section: Discussionmentioning

confidence: 99%

CTLs Contain and Use Intracellular Stores of FasL Distinct from Cytolytic Granules

Ostergaard

2007

The Journal of Immunology

View full text Add to dashboard Cite

CTL lyse target cells through the release of cytolytic granule contents and cell surface expression of Fas ligand (FasL). Current models suggest that FasL is stored in cytolytic granules and that FasL cell surface expression would be subject to the same controls as degranulation. We demonstrate that murine CTLs undergo two waves of FasL cell surface expression after stimulation. The first wave is from a pre-existing pool of FasL, and the second wave requires new protein synthesis. Signaling for FasL expression appears to be finely tuned as a weak signal preferentially induced surface translocation of the stored FasL, whereas a strong signal preferentially triggered the expression of de novo synthesized FasL. The early FasL is differentially regulated from degranulation, as there were multiple circumstances whereby rapid FasL cell surface expression and FasL-dependent killing occurred in the absence of detectable degranulation. Furthermore, we found through confocal microscopy that stored FasL resides in vesicles distinct from cytolytic granules. Our data clearly show that CTL degranulation and FasL lytic mechanisms are fully independent with respect to stored component localization and regulation.

show abstract

“…45 In fact, in other systems, PKC activation has also induced FasL gene transcription. 46 A predominant pathway of apoptosis in calvarial osteoblasts. 20,21,47,48 and brain 31,[49][50][51] is the Fas mediated pathway.…”

Section: Discussionmentioning

confidence: 99%

Nell-1 induces acrania-like cranioskeletal deformities during mouse embryonic development

Zhang

Cowan

Jiang

et al. 2006

Laboratory Investigation

View full text Add to dashboard Cite

We previously reported NELL-1 as a novel molecule overexpressed during premature cranial suture closure in patients with craniosynostosis (CS). Nell-1 overexpression also results in premature suture closure/ craniosynostosis in newborn transgenic mice. On a cellular level, increased levels of Nell-1 induce osteoblast differentiation and apoptosis. In this report, mice over-expressing Nell-1 were examined during embryonic development as well as shortly after birth for further analysis of craniofacial defects including neural tube defects (NTDs). The results demonstrated that overexpression of Nell-1 could induce acrania at relatively late gestation stage (E15.5) in mouse embryos, through massive apoptosis in calvarial osteoblasts and neural cells. The induced apoptosis was associated with an increase in Fas and Fas-L production. In addition, transgenic E15.5 and newborn transgenic mice with the CS phenotype displayed distortion of the chondrocranium associated with premature hypertrophy and increased apoptosis of chondrocytes. These findings were also verified in vitro with primary chondrocytes transduced with AdNell-1. In conclusion, Nell-1 overexpression can induce craniofacial anomalies associated with neural tube defects during embryonic development and may involve mechanisms of massive apoptosis associated with the Fas/Fas-L signaling pathway. NELL-1: used when describing the human gene; NELL-1: used when describing the human protein; Nell-1: used when describing the rodent gene; Nell-1: used when describing the rodent protein Laboratory Investigation (2006) 86, 633-644.

show abstract

Differential implication of protein kinase C isoforms in cytotoxic T lymphocyte degranulation and TCR-induced Fas ligand expression

Cited by 29 publications

References 57 publications

Duality of the murine CD8 compartment

Duality of the murine CD8 compartment

CTLs Contain and Use Intracellular Stores of FasL Distinct from Cytolytic Granules

Nell-1 induces acrania-like cranioskeletal deformities during mouse embryonic development

Contact Info

Product

Resources

About