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Induction of Alloantigen-specific Anergy in Human Peripheral Blood Mononuclear Cells by Alloantigen Stimulation with Co-stimulatory Signal Blockade
Published on: March 14, 2011
CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling
Gudrun Strauss1, Jonathan A Lindquist, Nathalie Arhel
1University Children's Hospital Ulm, 89075 Ulm, Germany. gudrun.strauss@uniklinik-ulm.de
Abstract:
CD95 is a multifunctional receptor that induces cell death or proliferation depending on the signal, cell type, and cellular context. Here, we describe a thus far unknown function of CD95 as a silencer of T cell activation. Naive human T cells triggered by antigen-presenting cells expressing a membrane-bound form of CD95 ligand (CD95L) or stimulated by anti-CD3 and -CD28 antibodies in the presence of recombinant CD95L had reduced activation and proliferation, whereas preactivated, CD95-sensitive T cells underwent apoptosis. Triggering of CD95 during T cell priming interfered with proximal T cell receptor signaling by inhibiting the recruitment of zeta-chain-associated protein of 70 kD, phospholipase-gamma, and protein kinase C- into lipid rafts, thereby preventing their mutual tyrosine protein phosphorylation. Subsequently, Ca(2+) mobilization and nuclear translocation of transcription factors NFAT, AP1, and NF-kappaB were strongly reduced, leading to impaired cytokine secretion. CD95-mediated inhibition of proliferation in naive T cells could not be reverted by the addition of exogenous interleukin-2 and T cells primed by CD95 co-stimulation remained partially unresponsive upon secondary T cell stimulation. HIV infection induced CD95L expression in primary human antigen-presenting cells, and thereby suppressed T cell activation, suggesting that CD95/CD95L-mediated silencing of T cell activation represents a novel mechanism of immune evasion.
Insights
CD95 (also known as Fas receptor) silences naive T cell activation by disrupting early signaling pathways. This novel function of CD95 highlights a potential mechanism for immune evasion, particularly in conditions like HIV infection.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- CD95 (Fas receptor) is a known inducer of apoptosis.
- Its role in regulating T cell activation has been less understood.
- Context-dependent signaling dictates CD95's diverse cellular outcomes.
Purpose of the Study:
- To elucidate a previously unrecognized function of CD95 in T cell biology.
- To investigate the molecular mechanisms by which CD95 influences T cell activation and proliferation.
- To explore the implications of CD95-mediated T cell silencing in immune responses and disease.
Main Methods:
- Utilized naive human T cells stimulated with antigen-presenting cells expressing CD95 ligand (CD95L) or with anti-CD3/CD28 antibodies plus recombinant CD95L.
- Analyzed proximal T cell receptor signaling events, including protein recruitment and phosphorylation within lipid rafts.
- Assessed calcium mobilization, transcription factor nuclear translocation (NFAT, AP1, NF-kappaB), and cytokine secretion.
- Investigated the effect of CD95 co-stimulation on T cell proliferation and responsiveness to secondary stimulation.
- Examined CD95L expression in antigen-presenting cells from HIV-infected individuals.
Main Results:
- CD95 triggering on naive T cells reduced activation and proliferation, while inducing apoptosis in preactivated T cells.
- CD95 signaling interfered with T cell receptor proximal signaling by inhibiting the assembly and phosphorylation of key signaling molecules (ZAP70, phospholipase-gamma, PKC) in lipid rafts.
- Impaired calcium mobilization and reduced nuclear translocation of NFAT, AP1, and NF-kappaB led to diminished cytokine secretion.
- CD95-induced inhibition of proliferation was IL-2-independent, and T cells primed with CD95 co-stimulation showed hyporesponsiveness upon secondary stimulation.
- HIV-infected individuals exhibited increased CD95L expression on antigen-presenting cells, correlating with suppressed T cell activation.
Conclusions:
- CD95 functions as a novel silencer of naive T cell activation, distinct from its role in apoptosis.
- The mechanism involves disruption of early T cell receptor signaling pathways, leading to impaired activation and proliferation.
- CD95/CD95L-mediated T cell silencing represents a potential immune evasion strategy, notably implicated in HIV pathogenesis.
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