ABSTRACT
The adaptor protein Bcl10 is a critically important mediator of T cell receptor (TCR)-to-NF-κB signaling. Bcl10 degradation is a poorly understood biological phenomenon suggested to reduce TCR activation of NF-κB. Here we have shown that TCR engagement triggers the degradation of Bcl10 in primary effector T cells but not in naive T cells. TCR engagement promoted K63 polyubiquitination of Bcl10, causing Bcl10 association with the autophagy adaptor p62. Paradoxically, p62 binding was required for both Bcl10 signaling to NF-κB and gradual degradation of Bcl10 by autophagy. Bcl10 autophagy was highly selective, as shown by the fact that it spared Malt1, a direct Bcl10 binding partner. Blockade of Bcl10 autophagy enhanced TCR activation of NF-κB. Together, these data demonstrate that selective autophagy of Bcl10 is a pathway-intrinsic homeostatic mechanism that modulates TCR signaling to NF-κB in effector T cells. This homeostatic process may protect T cells from adverse consequences of unrestrained NF-κB activation, such as cellular senescence.
Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Autophagy/physiology , NF-kappa B/metabolism , Receptors, Antigen, T-Cell/immunology , T-Lymphocyte Subsets/immunology , Adaptor Proteins, Signal Transducing/biosynthesis , Adaptor Proteins, Signal Transducing/genetics , Animals , Autophagy-Related Proteins , B-Cell CLL-Lymphoma 10 Protein , Caspases/physiology , Cell Differentiation , Cytosol/immunology , Cytosol/ultrastructure , Gene Expression Regulation/genetics , Gene Expression Regulation/immunology , Heat-Shock Proteins/biosynthesis , Heat-Shock Proteins/genetics , Heat-Shock Proteins/physiology , Homeostasis , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein , Neoplasm Proteins/physiology , Phagosomes/physiology , Phagosomes/ultrastructure , Protein Interaction Mapping , Sequestosome-1 Protein , Signal Transduction/genetics , Signal Transduction/immunology , T-Lymphocyte Subsets/ultrastructure , Th2 Cells/immunology , Th2 Cells/ultrastructure , Ubiquitin-Conjugating Enzymes/physiologyABSTRACT
AIM: To investigate the characterization of Th1/Th2 profile in patients with end-stage renal disease (ESRD) and the correlation with the apoptosis of the peripheral blood T cells; and to study the influence of different dialysis membranes on the apoptosis of T lymphocyte. METHODS: T cells from 10 non-dialyzed (ND) patients, 45 maintenance hemodialysis patients with cellulose acetate (CA) membrane, low-flux (PS-LF) and high-flux polusulfone (PS-HF) membrane, and 8 healthy volunteers (HC) were separated and stimulated with PHA for 24 hours in vitro. Then the apoptosis of T cells and supernatants levels of IFN-gamma and IL-4 were detected by Flow cytometry (FCM) and ELISA. RESULTS: In ESRD patients, the expression of Annexin V in T lymphocyte was higher than that of group HC (P<0.05), group CA was higher than group PS-HF and PS-LF (P<0.05). The level of IFN-gamma of ESRD patients was decreased significant compared with that in group HC (P<0.05), and there was negative correlation. between the Annexin V and IFN-gamma. IL-4 was increased in ESRD patients (P<0.05) and it was positive correlated with Annexin V. CONCLUSION: ESRD patients showed suppressed secretion of IFN-gamma, increased secretion of IL-4 and apoptosis of T lymphocytes.
Subject(s)
Apoptosis , Kidney Failure, Chronic/immunology , Kidney Failure, Chronic/pathology , Th1 Cells/immunology , Th1 Cells/pathology , Th2 Cells/immunology , Th2 Cells/pathology , Annexin A5/metabolism , Case-Control Studies , Female , Gene Expression Regulation , Humans , Interferon-gamma/metabolism , Interleukin-4/metabolism , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/metabolism , Leukocytes, Mononuclear/metabolism , Male , Microscopy, Electron, Transmission , Middle Aged , Th1 Cells/metabolism , Th1 Cells/ultrastructure , Th2 Cells/metabolism , Th2 Cells/ultrastructure , beta 2-Microglobulin/bloodABSTRACT
The bovine haemal nodes are lymphatic organs located in the haemal circulation. Their parenchyma is represented by plasma cells, macrophages and B and T lymphocytes. The T helper type 2 (Th2) CD4 lymphocyte can be found within the T lymphocytes. The activated Th2 CD4 lymphocyte produces interleukin-4 (IL-4), a peptidic hormone involved in the acute-phase immune response. This interleukin can promote either B-lymphocyte differentiation and T-lymphocyte proliferation or it can promote the type of immunoglobulin that can be liberated. Our results have shown, by immunostaining with anti-IL-4, not only the presence and localization of these lymphocytes in bovine haemal nodes but also the participation of polymorphonuclear cells (neutrophils) in the storage of IL-4. These results give value to the humoral and cellular immunological importance of haemal nodes in bovines and they can serve as a contribution to determine the cross-reactivity of bovine IL-4 with the human anti-serum used in this work.
