Glucocorticoids Attenuate T Cell Receptor Signaling

Laethem, François Van; Baus, Erika; Smyth, Lesley A.; Andris, Fabienne; Bex, Françoise; Urbain, Jacques; Kioussis, Dimitris; Léo, Oberdan

doi:10.1084/jem.193.7.803

Cited by 112 publications

(89 citation statements)

References 82 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: 88%

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: 88%

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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“…Similar disturbances of membrane rafts involving the displacement of Src family kinases and LAT apparently also contribute to the glucocorticoid-mediated inhibition of T cell signaling (50). Because dietary PUFAs are effectively incorporated into lymphocyte membrane lipids, altered LAT membrane subdomain distribution could also underlie the clinically apparent immunosuppressive action of PUFAs when these substances are applied to patients with inflammatory diseases.…”

Section: Pag-lat Chimeric Protein Is Retained In Rafts Of Pufaenrichementioning

confidence: 99%

LAT Displacement from Lipid Rafts as a Molecular Mechanism for the Inhibition of T Cell Signaling by Polyunsaturated Fatty Acids

Zeyda¹,

Staffler²,

Hořejšı́³

et al. 2002

Journal of Biological Chemistry

151

105

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Polyunsaturated fatty acids (PUFAs) suppress immune responses and inhibit T cell activation through largely unknown mechanisms. The displacement of signaling proteins from membrane lipid rafts has recently been suggested as underlying PUFA-mediated T cell inhibition. We show here that PUFA treatment specifically interferes with T cell signal transduction by blocking tyrosine phosphorylation of LAT (linker for activation of T cells) and phospholipase C␥1. A significant fraction of LAT was displaced from rafts by PUFA treatment along with other signaling proteins. However, retaining LAT alone in lipid rafts effectively restored phospholipase C␥1/calcium signaling in PUFA-treated T cells. These data reveal LAT displacement from lipid rafts as a molecular mechanism by which PUFAs inhibit T cell signaling and underline the predominant importance of LAT localization in rafts for efficient T cell activation. Polyunsaturated fatty acids (PUFAs)1 suppress immune responses (1) and are clinically applied as adjuvant immunosuppressive agents in the treatment of inflammatory disorders (e.g. rheumatoid arthritis and inflammatory bowel disease) (2, 3) and following organ transplantation (4). PUFAs of the n-3 series have been shown to be particularly effective and are known to interfere with proinflammatory eicosanoid (prostaglandin/leukotriene) synthesis (1). However, PUFA-mediated inhibition of T lymphocyte activation and function has repeatedly been shown to be independent of eicosanoid synthesis (5-8). The molecular mechanism by which PUFAs inhibit T cell signal transduction has remained largely unknown. Because PUFA treatment changes the lipid composition of lymphocyte membranes (9) and functionally important membrane lipid rafts (10), alterations of rafts have been suggested as underlying the PUFA-mediated inhibition of T cell signaling (11).Membrane lipid rafts or microdomains are specialized regions within the plane of the plasma membrane and have been proposed as playing an essential role in T cell signal transduction (12-16). Lipid rafts are characterized by a high concentration of cholesterol and sphingolipids such as sphingomyelin and glycolipids, and their polar lipids contain predominantly saturated fatty acyl residues (17, 18). Such lipids spontaneously form liquid-ordered membrane regions that are insoluble in non-ionic detergents, facilitating raft isolation as detergentresistant membrane domains (18,19). Cytoplasmic and transmembrane proteins are targeted to lipid rafts mostly by acylation with saturated fatty acyl moieties (palmitoyl and myristoyl) which link these proteins to the cytoplasmic lipid leaflet of microdomains (20). Several proteins involved in T cell signaling such as Src family protein-tyrosine kinases (PTKs) and LAT (linker for activation of T cells) are concentrated in rafts because of post-translational palmitoylation, emphasizing the role of lipid rafts in T cell signaling (14, 21).The activation of T cells requires stimulation of the T cell antigen receptor (TCR)/CD3 complex. Triggering CD3...

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“…Their mechanism of action is diverse and includes interference with intracellular transcription factors and signaling pathways of several surface receptors, including the T cell antigen receptor 52 and downstream kinases. 53 High doses of corticosteroids (.1 mg/kg), used for induction therapy in transplantation, also induce lymphocyte apoptosis (including B cells) 46,54 and can prevent in vitro differentiation of B cells into plasma cells.…”

Section: Corticosteroidsmentioning

confidence: 99%

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Thaunat

Koenig

Leibler³

et al. 2016

JASN

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The negative effect of donor-specific antibodies on the success of solid transplant is now clearly established. However, the lack of effective treatment to prevent the development of antibody-mediated lesions deepens the need for clinicians to focus on primary prevention of de novo humoral allosensitization. Among the factors associated with the risk of developing de novo donor-specific antibodies, therapeutic immunosuppression is the most obvious parameter in which improvement is possible. Beyond compliance and the overall depth of immunosuppression, it is likely that the nature of the drugs is also crucial. Here, we provide an overview of the molecular effect of the various immunosuppressive drugs on B cell biology. Clinical data related to the effect of these drugs on de novo humoral allosensitization are also examined, providing a platform from which clinicians can optimize immunosuppression for prevention of de novo donor-specific antibody generation at the individual level.

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Glucocorticoids Attenuate T Cell Receptor Signaling

Cited by 112 publications

References 82 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

LAT Displacement from Lipid Rafts as a Molecular Mechanism for the Inhibition of T Cell Signaling by Polyunsaturated Fatty Acids

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

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