It has been appreciated for more than three decades that the interactions between the T-cell antigen receptor and self-antigens are the major determinants of the cell fates of developing thymocytes and the establishment of central tolerance. However, recent evidence shows that the level of self-reactivity substantially contributes to fate choices of positively selected mature T cells in homeostasis, as well as during immune responses. This implies that individual clones of peripheral T cells are predisposed to specific functional properties based on the self-reactivity of their antigen receptors. Overall, the relative difference in the self-reactivity among peripheral T cells is an important factor contributing to the diversity of T-cell responses to foreign antigens.

• MeSH
• Lymphocyte Activation immunology   MeSH
• Autoantigens immunology   MeSH
• CD4-Positive T-Lymphocytes immunology   metabolism   MeSH
• CD8-Positive T-Lymphocytes immunology   metabolism   MeSH
• Nuclear Receptor Subfamily 4, Group A, Member 1 immunology   metabolism   MeSH
• Humans MeSH
• Receptors, Antigen, T-Cell immunology   metabolism   MeSH
• Thymocytes cytology   immunology   MeSH
• Thymus Gland cytology   immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Purpose: Among other reasons, the deteriorating global security situation and dangers associated with nuclear weapons have increased the need for deeper knowledge of the basic mechanisms involving the human immune system and ionizing radiation (IR). We conducted a review as to the effects of IR on thymic tissue, and particularly on the development of thymocytes and the T lymphocytes population in peripheral blood. Existing knowledge on this topic is based in part on national registers that store records concerning irradiated people. The majority of studies in this area, however, are based on experimental animal models. The main open question in this subject area regards the delayed effects of IR on thymus tissue, development of thymocytes, and subsequent impact on the immune system. Findings acquired to date on effects of IR are contributing to emerging fields such as immunotherapy, the objective of which is to support or activate natural immunity response. Methods: Recent research articles were reviewed regarding the influence of IR on thymus tissue and thymocytes development. Results: Differentiation and proliferation of thymocytes constitute a complex and sensitive process that is partially altered after irradiation, as are, too, the mechanisms for movement of early (derived from bone marrow) and derived (thymus derivatives) precursors. Disruption of these processes may lead to alteration of immune system function. Conclusions: Low doses (<200 mGy) may lead to changes in or disruption of functions of the thymus, thymocytes, and mechanisms of the immune system. The extent of IR’s influence is dependent not only on the individual’s radiosensitivity but also on his or her sex and age. With increasing absorbed IR dose, the risk of damage to thymus tissue and thymocytes in the organism rises and the extent of damage increases.

• MeSH
• Radiation Dosage MeSH
• Hematopoiesis radiation effects   MeSH
• Immune System radiation effects   MeSH
• Radiation, Ionizing * MeSH
• Humans MeSH
• Lymphocytes radiation effects   MeSH
• Radiation Exposure * adverse effects   MeSH
• Radiation Effects MeSH
• Re-Irradiation MeSH
• Thymocytes radiation effects   MeSH
• Thymus Gland radiation effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Genome integrity is protected by the cell-cycle checkpoints that prevent cell proliferation in the presence of DNA damage and allow time for DNA repair. The transient checkpoint arrest together with cellular senescence represent an intrinsic barrier to tumorigenesis. Tumor suppressor p53 is an integral part of the checkpoints and its inactivating mutations promote cancer growth. Protein phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of p53. Although its loss impairs recovery from the G2 checkpoint and promotes induction of senescence, amplification of the PPM1D locus or gain-of-function truncating mutations of PPM1D occur in various cancers. Here we used a transgenic mouse model carrying a truncating mutation in exon 6 of PPM1D (Ppm1dT). As with human cell lines, we found that the truncated PPM1D was present at high levels in the mouse thymus. Truncated PPM1D did not affect differentiation of T-cells in the thymus but it impaired their response to ionizing radiation (IR). Thymocytes in Ppm1dT/+ mice did not arrest in the checkpoint and continued to proliferate despite the presence of DNA damage. In addition, we observed a decreased level of apoptosis in the thymi of Ppm1dT/+ mice. Moreover, the frequency of the IR-induced T-cell lymphomas increased in Ppm1dT/+Trp53+/- mice resulting in decreased survival. We conclude that truncated PPM1D partially suppresses the p53 pathway in the mouse thymus and potentiates tumor formation under the condition of a partial loss of p53 function.

• MeSH
• Apoptosis * MeSH
• Cell Cycle MeSH
• Radiation, Ionizing MeSH
• Lymphoma metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Tumor Suppressor Protein p53 metabolism   MeSH
• Neoplasms, Radiation-Induced metabolism   MeSH
• DNA Repair MeSH
• DNA Damage MeSH
• Cell Proliferation MeSH
• Protein Phosphatase 2C physiology   MeSH
• Thymocytes cytology   metabolism   MeSH
• Thymus Gland * cytology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Porcine reproductive and respiratory syndrome virus (PRRSV) causes immune dysregulation during the Critical Window of Immunological Development. We hypothesize that thymocyte development is altered by infected thymic antigen presenting cells (TAPCs) in the fetal/neonatal thymus that interact with double-positive thymocytes causing an acute deficiency of T cells that produces "holes" in the T cell repertoire allowing for poor recognition of PRRSV and other neonatal pathogens. The deficiency may be the result of random elimination of PRRSV-specific T cells or the generation of T cells that accept PRRSV epitopes as self-antigens. Loss of helper T cells for virus neutralizing (VN) epitopes can result in the failure of selection for B cells in lymph node germinal centers capable of producing high affinity VN antibodies. Generation of cytotoxic and regulatory T cells may also be impaired. Similar to infections with LDV, LCMV, MCMV, HIV-1 and trypanosomes, the host responds to the deficiency of pathogen-specific T cells and perhaps regulatory T cells, by "last ditch" polyclonal B cell activation. In colostrum-deprived PRRSV-infected isolator piglets, this results in hypergammaglobulinemia, which we believe to be a "red herring" that detracts attention from the thymic atrophy story, but leads to our second independent hypothesis. Since hypergammaglobulinemia has not been reported in PRRSV-infected conventionally-reared piglets, we hypothesize that this is due to the down-regulatory effect of passive maternal IgG and cytokines in porcine colostrum, especially TGFβ which stimulates development of regulatory T cells (Tregs).

• MeSH
• Hypergammaglobulinemia blood   etiology   metabolism   MeSH
• Immunoglobulin Isotypes blood   immunology   MeSH
• Host-Pathogen Interactions immunology   MeSH
• Disease Susceptibility MeSH
• Pandemics MeSH
• Swine MeSH
• Antibodies, Viral blood   immunology   MeSH
• Porcine Reproductive and Respiratory Syndrome blood   epidemiology   etiology   MeSH
• T-Lymphocytes cytology   immunology   metabolism   MeSH
• Thymocytes cytology   immunology   metabolism   MeSH
• Thymus Gland immunology   metabolism   MeSH
• Porcine respiratory and reproductive syndrome virus physiology   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Development of lymphoid progenitors requires a coordinated regulation of gene expression, DNA replication, and gene rearrangement. Chromatin-remodeling activities directed by SWI/SNF2 superfamily complexes play important roles in these processes. In this study, we used a conditional knockout mouse model to investigate the role of Smarca5, a member of the ISWI subfamily of such complexes, in early lymphocyte development. Smarca5 deficiency results in a developmental block at the DN3 stage of αβ thymocytes and pro-B stage of early B cells at which the rearrangement of Ag receptor loci occurs. It also disturbs the development of committed (CD73+) γδ thymocytes. The αβ thymocyte block is accompanied by massive apoptotic depletion of β-selected double-negative DN3 cells and premitotic arrest of CD4/CD8 double-positive cells. Although Smarca5-deficient αβ T cell precursors that survived apoptosis were able to undergo a successful TCRβ rearrangement, they exhibited a highly abnormal mRNA profile, including the persistent expression of CD44 and CD25 markers characteristic of immature cells. We also observed that the p53 pathway became activated in these cells and that a deficiency of p53 partially rescued the defect in thymus cellularity (in contrast to early B cells) of Smarca5-deficient mice. However, the activation of p53 was not primarily responsible for the thymocyte developmental defects observed in the Smarca5 mutants. Our results indicate that Smarca5 plays a key role in the development of thymocytes undergoing β-selection, γδ thymocytes, and also B cell progenitors by regulating the transcription of early differentiation programs.

• MeSH
• Adenosine Triphosphatases genetics   metabolism   MeSH
• B-Lymphocytes physiology   MeSH
• Cell Differentiation MeSH
• Chromosomal Proteins, Non-Histone genetics   metabolism   MeSH
• Gene Rearrangement MeSH
• Clonal Selection, Antigen-Mediated MeSH
• Cells, Cultured MeSH
• Lymphoid Progenitor Cells physiology   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Tumor Suppressor Protein p53 metabolism   MeSH
• Receptors, Antigen, B-Cell genetics   metabolism   MeSH
• Receptors, Antigen, T-Cell, alpha-beta genetics   metabolism   MeSH
• Receptors, Antigen, T-Cell, gamma-delta genetics   metabolism   MeSH
• T-Lymphocytes physiology   MeSH
• Thymocytes physiology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Antibodies of non-human mammals are glycosylated with carbohydrate antigens, such as galactose-α-1-3-galactose (α-Gal) and N-glycolylneuraminic acid (Neu5Gc). These non-human carbohydrate antigens are highly immunogenic in humans due to loss-of-function mutations of the key genes involved in their synthesis. Such immunogenic carbohydrates are expressed on therapeutic polyclonal rabbit anti-human T-cell IgGs (anti-thymocyte globulin; ATG), the most popular induction treatment in allograft recipients. To decipher the quantitative and qualitative response against these antigens in immunosuppressed patients, particularly against Neu5Gc, which may induce endothelial inflammation in both the graft and the host. We report a prospective study of the antibody response against α-Gal and Neu5Gc-containing glycans following rabbit ATG induction compared to controls. We show a drop in the overall levels of anti-Neu5Gc antibodies at 6 and 12 months post-graft compared to the pre-existing levels due to the major early immunosuppression. However, in contrast, in a cross-sectional study there was a highly significant increase in anti-Neu5Gc IgGs levels at 6 months post-graft in the ATG-treated compared to non-treated patients(P = 0.007), with a clear hierarchy favouring anti-Neu5Gc over anti-Gal response. A sialoglycan microarray analysis revealed that the increased anti-Neu5Gc IgG response was still highly diverse against multiple different Neu5Gc-containing glycans. Furthermore, some of the ATG-treated patients developed a shift in their anti-Neu5Gc IgG repertoire compared with the baseline, recognizing different patterns of Neu5Gc-glycans. In contrast to Gal, Neu5Gc epitopes remain antigenic in severely immunosuppressed patients, who also develop an anti-Neu5Gc repertoire shift. The clinical implications of these observations are discussed.

• MeSH
• Immunity, Cellular physiology   MeSH
• Adult MeSH
• Transplantation, Homologous MeSH
• Immunoglobulin G pharmacology   MeSH
• Immunologic Factors pharmacology   MeSH
• Neuraminic Acids immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Prospective Studies MeSH
• Antibodies immunology   metabolism   MeSH
• Cross-Sectional Studies MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Thymocytes immunology   MeSH
• Kidney Transplantation methods   MeSH
• Transplantation Immunology physiology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Cytomegalovirus (CMV) infection influences both short and long term outcomes in immunosuppressed organ transplant recipients. The aim of this study was to evaluate the effect of different induction immunosuppression regimens on CMV specific T cell response in patients with already established CMV immunity. In 24 seropositive living donor kidney recipients, the frequency of CMV specific T cells was determined by ELISPOT (Enzyme-Linked ImmunoSpot) assay prior and 6 months after transplantation. Recipients' peripheral blood mononuclear cells were stimulated with immediate-early (IE1) and phosphoprotein 65 (pp65) CMV-derived peptide pools and the number of cells producing interferon gamma (IFN-gamma) was assessed. Patients received quadruple immunosuppression based either on depletive rabbit antithymocyte globulin (rATG) or non-depletive basiliximab induction and tacrolimus/mycophenolate mofetil/steroids. Patients with rATG induction received valgancyclovir prophylaxis. No effects of different induction agents on CMV specific T cell immunity were found at sixth month after kidney transplantation. There were no associations among dialysis vintage, pretransplant CMV specific T cell immunity, and later CMV DNAemia. Similarly, no effect of CMV prophylaxis on CMV specific T cell immunity was revealed. This study shows no effect of posttransplant immunosuppression on CMV specific T cell immunity in living donor kidney transplant recipients with CMV immunity already established, regardless of lymphocyte depletion and CMV prophylaxis.

• MeSH
• Immunity, Cellular MeSH
• Cytomegalovirus Infections prevention & control   MeSH
• Cytomegalovirus immunology   MeSH
• Adult MeSH
• Phosphoproteins immunology   MeSH
• Immunosuppressive Agents therapeutic use   MeSH
• Immunosuppression Therapy methods   MeSH
• Induction Chemotherapy MeSH
• Middle Aged MeSH
• Humans MeSH
• Monitoring, Immunologic MeSH
• Viral Matrix Proteins immunology   MeSH
• T-Lymphocytes immunology   MeSH
• Thymocytes immunology   MeSH
• Kidney Transplantation methods   MeSH
• Living Donors * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The RLTPR cytosolic protein, also known as CARMIL2, is essential for CD28 co-stimulation in mice, but its importance in human T cells and mode of action remain elusive. Here, using affinity purification followed by mass spectrometry analysis, we showed that RLTPR acts as a scaffold, bridging CD28 to the CARD11/CARMA1 cytosolic adaptor and to the NF-κB signaling pathway, and identified proteins not found before within the CD28 signaling pathway. We further demonstrated that RLTPR is essential for CD28 co-stimulation in human T cells and that its noncanonical pleckstrin-homology domain, leucine-rich repeat domain, and proline-rich region were mandatory for that task. Although RLTPR is thought to function as an actin-uncapping protein, this property was dispensable for CD28 co-stimulation in both mouse and human. Our findings suggest that the scaffolding role of RLTPR predominates during CD28 co-stimulation and underpins the similar function of RLTPR in human and mouse T cells. Along that line, the lack of functional RLTPR molecules impeded the differentiation toward Th1 and Th17 fates of both human and mouse CD4(+) T cells. RLTPR was also expressed in both human and mouse B cells. In the mouse, RLTPR did not play, however, any detectable role in BCR-mediated signaling and T cell-independent B cell responses.

• MeSH
• Amino Acid Motifs MeSH
• CD28 Antigens metabolism   MeSH
• Models, Biological MeSH
• Killer Cells, Natural metabolism   MeSH
• Dendritic Cells metabolism   MeSH
• Endocytosis MeSH
• Gene Targeting MeSH
• HEK293 Cells MeSH
• Jurkat Cells MeSH
• Humans MeSH
• Lymphocytes metabolism   MeSH
• Protein Interaction Mapping MeSH
• Microfilament Proteins chemistry   metabolism   MeSH
• Protein Multimerization MeSH
• Mutation genetics   MeSH
• Myeloid Cells metabolism   MeSH
• Mice MeSH
• Protein Domains MeSH
• Proteomics MeSH
• T-Lymphocytes, Regulatory metabolism   MeSH
• Signal Transduction MeSH
• T-Lymphocytes metabolism   MeSH
• Thymocytes metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

T regulatory cells (Tregs) are essential for maintaining tolerance and preventing autoimmune diseases, such as type 1 diabetes (T1D). In our study, we investigated CD25 + FoxP3 + Tregs and thymic FoxP3 + Helios + Tregs in large cohorts of children with T1D at onset and with long-term T1D, and further in their relatives and healthy controls. We observed significantly decreased numbers of CD25 + FoxP3 + Tregs, but not FoxP3 + Helios + Tregs, in long-term patients compared with the control group and T1D onset. Furthermore, long-term T1D patients exhibited highly significant decrease of CD25 expression on both CD25 + FoxP3 + Tregs and FoxP3 + Helios + Tregs, independently on age or the duration of diabetes. A similar reduction of CD25 expression was also found in T1D relatives, more significant in those with positive autoantibodies. Low CD25 expression was associated with impaired signal transducer and activator of transcription 5 (STAT5) phosphorylation after IL-2 exposure. Our results show that the frequency of Tregs is altered in a large cohort of long-term T1D patients, a profound decrease in CD25 expression and altered IL-2 signaling are typical features of Tregs populations in long-term diabetic patients and their relatives.

• MeSH
• Biomarkers MeSH
• Cell Differentiation MeSH
• Diabetes Mellitus, Type 1 diagnosis   etiology   metabolism   MeSH
• Child MeSH
• Forkhead Transcription Factors metabolism   MeSH
• Phosphorylation MeSH
• Immunophenotyping MeSH
• Interleukin-2 metabolism   pharmacology   MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Lymphocyte Count MeSH
• Child, Preschool MeSH
• Interleukin-2 Receptor alpha Subunit genetics   metabolism   MeSH
• T-Lymphocytes, Regulatory cytology   immunology   metabolism   MeSH
• Signal Transduction MeSH
• Case-Control Studies MeSH
• Thymocytes cytology   immunology   metabolism   MeSH
• STAT5 Transcription Factor MeSH
• Age Factors MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Mancozeb, as a dithiocarbamate fungicide, has been found to exhibit toxicological manifestations in different cells, mainly by generation of free radicals which may alter antioxidant defence systems in cells. The effect of mancozeb on the cells of a primary lymphoid organ has not been studied. In the present study, the effects of mancozeb (0.2, 2 and 5 μg/ml) or mancozeb+ascorbic acid (100 μg/ml), or ascorbic acid alone or control medium alone on the levels of cell viability, apoptosis, intracellular reactive oxygen species production (ROS), mitochondrial membrane potential (MMP) and ATP levels in rat thymocytes were examined in vitro. Cells treated with mancozeb displayed a concentration-dependent increase of hypodiploid cells and ROS production followed by markedly decreased viability of the cells, MMP and ATP levels. Application of ascorbic acid significantly reduced cytotoxicity in cell cultures treated with 0.2 and 2 μg/ml of mancozeb, together with significantly decreased ROS levels and increased MMP and ATP levels. In cells treated with 5 μg/ml of mancozeb, ascorbic acid failed to reduce toxicity while simultaneously increasing the apoptosis rate of thymocytes. These results suggest that ROS plays a significant role in mancozeb-induced toxicity, through alteration of mitochondrial function. Ascorbic acid administration reduced the toxicity rate in cells treated with lower mancozeb concentrations, while it may have the ability to shift cells from necrosis to apoptosis in the presence of highest mancozeb concentrations.

• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Antioxidants administration & dosage   pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Biomarkers metabolism   MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Ascorbic Acid administration & dosage   pharmacology   MeSH
• Maneb administration & dosage   toxicity   MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Oxidative Stress drug effects   MeSH
• Rats, Wistar MeSH
• Fungicides, Industrial administration & dosage   toxicity   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Thymocytes drug effects   metabolism   MeSH
• Cell Survival drug effects   MeSH
• Zineb administration & dosage   toxicity   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Evaluation Study MeSH