Propriocidal apoptosis of mature T lymphocytes occurs at S phase of the cell cycle

Anergic T cells have immunoregulatory activity and can survive for extended periods in vivo. It is unclear how anergic T cells escape from deletion, because both anergy and apoptosis can occur after TCR ligation. Stimulation of human CD4+ T cell clones reactive to influenza hemagglutinin peptides can occur in the absence of APCs when MHC class II-expressing, activated T cells present peptide to each other. This T:T peptide presentation can induce CD95-mediated apoptosis, while the cells that do not die are anergic. We found that the death after peptide or anti-CD3 treatment of a panel of CD4+ T cell clones is blocked by IFN-β secreted by fibroblasts and also by IFN-α. This increases cell recovery after stimulation, which is not due to T cell proliferation. This mechanism for apoptosis inhibition rapidly stops protein kinase C-δ translocation from the cytoplasm to the nucleus, which is an early event in the death process. A central observation was that CD4+ T cells that are rescued from apoptosis after T:T presentation of peptide by IFN-αβ remain profoundly anergic to rechallenge with Ag-pulsed APCs. However, anergized cells retain the ability to respond to IL-2, showing that they are nonresponsive but functional. The prevention of peptide-induced apoptosis in activated T cells by IFN-αβ is a novel mechanism that may enable the survival and maintenance of anergic T cell populations after TCR engagement. This has important implications for the persistence of anergic T cells with the potential for immunoregulatory function in vivo.

Section: Ifn-␤ Is the Main Anti-apoptotic Mediator In Fcmsupporting

confidence: 71%

Type 1 IFN Maintains the Survival of Anergic CD4+ T Cells

Lombardi

Dunne

Scheel‐Toellner

et al. 2000

“…It has been reported that the B cell marker B220 is up-regulated on activated T cell blasts before entering apoptosis (27,35,36). Considering that nasal tissues are an overexposed environment, it can be hypothesized that cells from NALT undergo apoptosis after activation by exogenous Ags or superantigen, as previously demonstrated in other experimental systems (27,35,37,38). However, the expression levels of both CD45RB and activation markers suggests that the majority of cells from NALT corresponded to naive T cells (CD45RB high ).…”

Section: Discussionmentioning

confidence: 83%

Characterization of a B220+ Lymphoid Cell Subpopulation with Immune Modulatory Functions in Nasal-Associated Lymphoid Tissues

Rharbaoui¹,

Bruder²,

Vidaković

et al. 2005

Complex mechanisms operate on mucosal tissues to regulate immune responsiveness and tolerance. When the lymphocyte subpopulations from murine nasal-associated lymphoid tissues (NALT) were characterized, we observed an accumulation of B220lowCD3lowCD4−CD8−CD19−c-Kit+ cells. TCR transgenic mice and athymic mice were used for monitoring T cell lineage and the presence of extrathymic T cell precursors. The majority of cells from NALT exhibited a T cell precursor phenotype (CD4−CD8−CD19−c-Kit+). Fas-independent apoptosis was their main mechanism of cell death. We also demonstrated that B220lowCD4−CD8−CD19− cells from NALT exhibited the potential to down-regulate the activation of mature T cells. However, the innate immunity receptor TLR2 was also highly expressed by this cell subpopulation. Moreover, nasal stimulation with a TLR2/6 agonist resulted in a partial activation of the double-negative cells. These results suggest that the immune responses in NALT may be in part modulated by a cell subpopulation that maintains a tolerogenic milieu by its proapoptotic status and suppressive activity, which can be reverted through stimulation of a TLR signaling cascade.

“…After overnight culture, thymocytes were harvested, and cell death was measured as previously described (27)(28)(29). These previous studies have shown that this method accurately assesses cell loss resulting from T cell apoptosis.…”

Section: In Vitro Cell Death Assaymentioning

confidence: 99%

Opening a Window on Thymic Positive Selection: Developmental Changes in the Influence of Cosignaling by Integrins and CD28 on Selection Events Induced by TCR Engagement

Lucas

Germain

2000

How TCR and non-TCR signals are integrated by thymocytes to generate a decision to undergo either positive or negative selection remains incompletely understood. Recent evidence suggests that TCR signal transduction changes its quality during thymocyte maturation, but whether the contributions of various cosignaling or costimulatory pathways to thymocyte selection also are modified during development is unclear. Questions also remain about the possible selective roles of specific costimulatory pathways in induction of differentiation vs death among thymocytes at any given stage of maturity. To address these issues, a quantitative in vitro analysis of initiation of CD4+CD8+ thymocyte differentiation as measured by CD69 up-regulation/coreceptor down-modulation was conducted in parallel with an analysis of induction of death. Using transfected cells varying in their surface display of ICAM-1 or B7.1 along with antibody blocking experiments, we demonstrate here that ICAM-1 provides a selective boost to signaling for differentiation without substantially affecting induction of death among CD4+CD8+ cells, a property that is lost as thymocytes mature further. In contrast, B7 engagement enhances both cell activation and death in parallel. Based on these data, we propose that the high level of ICAM-1 on cortical epithelial cells plays a special role in opening a window between TCR signaling for differentiation vs death, permitting efficient initiation of positive selection on epithelial ligands. In contrast, late CD28-dependent cosignaling on hemopoietic cells in the medulla would help enforce negative selection by augmenting the effects of TCR engagement by low levels of high affinity ligands.