Dexamethasone Modulates TCR ζ Chain Expression and Antigen Receptor-Mediated Early Signaling Events in Human T Lymphocytes

Nambiar, Madhusoodana P.; Enyedy, Edith J.; Fisher, Carolyn U.; Warke, Vishal G.; Juang, Yuang-Taung; Tsokos, George C.

doi:10.1006/cimm.2001.1761

Cited by 22 publications

(16 citation statements)

References 29 publications

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“…There are numerous in vivo and in vitro reports on corticosteroids and their analogues which effect thymocyte apoptotsis and which also have adverse effects on peripheral T cell activation events. [76][77][78][79][80][81][82] However, a previous study by Wienberg et al 34 demonstrated that TREC levels increased in cord blood transplant recipients even while receiving low-dose steroids as GVHD prophylaxis. However, this data does not exclude the possibility that high dose corticosteroids used in GVHD treatment would have an adverse effect on thymic output.…”

Section: Discussionmentioning

confidence: 97%

Factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients

Fallen

McGreavey

Madrigal

et al. 2003

Bone Marrow Transplant

105

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Summary:The factors affecting T cell reconstitution post haematopoietic cell transplantation (HCT) are not well characterised. We carried out a longitudinal analysis of T cell reconstitution in 32 HCT recipients during the first 12 months post transplant. We analysed reconstitution of naı¨ve, memory and effector T cells, their diversity and monitored thymic output using TCR rearrangement excision circles (TRECs). Thymic-independent pathways were responsible for the rapid reconstitution of memory and effector T cells less than 6 months post HCT. Thymic-dependent pathways were activated between 6 and 12 months in the majority of patients with naı¨ve T cell numbers increasing in parallel with TREC levels. Increasing patient age, chronic GVHD and T cell depletion (with or without pretransplant Campath-1H) predicted low TREC levels and slow naı¨ve T cell recovery. Furthermore, increasing patient age also predicted high memory and effector T cell numbers. The effects of post HCT immunosuppression, total body irradiation, donor leucocyte infusions, T cell dose and post HCT infections on T cell recovery were also analysed. However, no effects of these single variables across a variety of different age, GVHD and T cell depletion groups were apparent. This study suggests that future analysis of the factors affecting T cell reconstitution and studies aimed at reactivating the thymus through therapeutic intervention should be analysed in age-, GVHD-and TCD-matched patient groups. While each of these parameters may have mutually exclusive effects on the outcome of the transplant, it is the combination of all of these parameters that will determine the ultimate success of the transplant. Furthermore, the effects of each of these parameters on immune reconstitution post HCT are unclear.The immediate post transplant period is followed by a severe and often prolonged immune deficiency that results in prolonged susceptibility to infection. 8,17,[19][20][21][22] Although infections that occur in the first month after engraftment probably result from deficiencies in both granulocytes and other mononuclear cell subsets, the more prolonged immune deficiency arises from deficiencies in effective CD4 þ T cell and B cell reconstitution and immunosuppressive therapy. 23,[27][28][29] It was then suggested that the reconstitution and maintenance of effective T cell immunity after HCT was dependent on education of T cell precursors in the thymus. [30][31][32] Furthermore, these observations generated considerable interest in the factors affecting the reconstitution of T cell immunity through thymic-dependent pathways. 33,34 Using phenotypic markers of T cell naivety (primarily the CD45RA antigen), initial studies demonstrated that increasing patient age had an adverse effect on the regeneration of naı¨ve CD4 þ T cells, presumably due to age-related thymic involution, 31 observations that were confirmed using the TCR rearrangement excision circle (TREC) assay to measure thymic output. 35,36 In addition, the thymus has been demonstrated to be...

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Section: Discussionmentioning

confidence: 97%

Factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients

Fallen

McGreavey

Madrigal

et al. 2003

Bone Marrow Transplant

105

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“…Immunoblotting with 100-fold excess N-terminal peptide inhibited the binding of the mAb to the 14-kd form, suggesting that it is TCR chain specific. The 14-kd form of the chain could be an alternatively spliced isoform lacking exon VII, since the finding of increased levels of TCR chain mRNA lacking exon VII in patients with SLE has been reported (7,12,34). A second possibility is that the 14-kd isoform of the chain is a product of proteolytic degradation, because there are few potential caspase cleavage sites in the TCR chain (Figure 1).…”

Section: Nambiar Et Almentioning

confidence: 98%

“…Crosslinking of the T cell receptor (TCR)/CD3 complex of SLE T cells leads to a disease-specific increase in [Ca 2ϩ ] i responses (10) and tyrosine phosphorylation of cytosolic protein substrates (3,8). Recently, we identified a decrease in the expression of TCR chain messenger RNA (mRNA) and the detergent-soluble form of TCR chain in a majority of SLE patients (3,11,12). Defective expression of the chain at both the protein and mRNA levels has also been reported by others (7,9).…”

mentioning

confidence: 99%

“…Recently, an alternatively spliced isoform of the chain with an insertion of glutamine at position 100, that is expressed equally in normal and SLE T cells, has been described (12,33). Expression of alternatively spliced isoforms of the chain with insertion or deletion of various exons or combinations of exons in SLE T cells has been reported (7,11,12,34). Although abnormalities in the expression of the detergent-soluble 16-kd form of the chain have been found in SLE, a complete spectrum of the expression of different forms of the TCR chain has not been reported.…”

mentioning

confidence: 99%

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Abnormal expression of various molecular forms and distribution of T cell receptor ? chain in patients with systemic lupus erythematosus

Nambiar

Enyedy

Fisher

et al. 2002

Arthritis & Rheumatism

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“…T cell ζ chain deficiency is persistent over time and is independent of SLE disease activity and treatment [12,13]. Cloning and sequencing of genomic DNA and TCR ζ transcripts revealed widely divergent mutations and silent polymorphism in the coding region in lupus T cells.…”

Section: Abnormal Tcr Activation and Ca 2+ Signaling In Slementioning

confidence: 99%

The role of nitric oxide in abnormal T cell signal transduction in systemic lupus erythematosus

Nagy

Perl

2006

Clinical Immunology

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by production of antinuclear autoantibodies and diverse array of clinical manifestations. T cells from patients with SLE have been shown to be activated in vivo and provide help to autoreactive B cells. Lupus T cells exhibit enhanced spontaneous and diminished activation-induced apoptosis and predisposition to necrosis. Persistent mitochondrial hyperpolarization and ATP depletionassociated with significantly increased mitochondrial mass -characterize T lymphocyte dysfunction in SLE. In addition to cell death abnormalities, mitochondrial dysfunction is associated with altered signal transduction through the T cell receptor and Ca 2+ fluxing. Exposure of normal T cell to nitric oxide induces mitochondrial hyperpolarization and biogenesis and regenerates the Ca 2+ signaling profile of lupus T cells. This article reviews a novel understanding of the role of nitric oxide in signal transduction and cell death abnormalities in SLE.

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Dexamethasone Modulates TCR ζ Chain Expression and Antigen Receptor-Mediated Early Signaling Events in Human T Lymphocytes

Cited by 22 publications

References 29 publications

Factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients

Factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients

Abnormal expression of various molecular forms and distribution of T cell receptor ? chain in patients with systemic lupus erythematosus

The role of nitric oxide in abnormal T cell signal transduction in systemic lupus erythematosus

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