Peripheral T‐Cell Reactivity to Bacterial Superantigens <i>in vivo:</i> The Response/Anergy Paradox

MacDonald, H. Robson; Lees, Rosemary K.; Baschieri, Selene; Herrmann, Thomas; Lussow, A R

doi:10.1111/j.1600-065x.1993.tb01512.x

Cited by 64 publications

(46 citation statements)

References 71 publications

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“…A model that may explain our results is that in addition to activating large numbers T cells in vivo and stimulating the release of large quantities of cytokines (1)(2)(3)(4)(5)(6), injected SEA may also promote activated neutrophils and macrophages to colocalize with the responding T cells in an inflammatory site in the spleens of the SAg-treated animals. We postulate that once the conditions for suppression have been established in vivo, subsequent antigenic restimulation in vitro promotes further IFN-␥ production, stimulating small numbers of Gr-1 ϩ cells in the enriched T cell cultures to produce a combination of RNI and ROI.…”

Section: Discussionmentioning

confidence: 96%

“…However, the response peaks about 3 days after the SAg is injected and then declines abruptly, leaving diminished populations of SAg-reactive CD4 T cells in the periphery of the SAgtreated animals. In some studies, the residual SAg-reactive T cells were hyporesponsive to restimulation (6). Secondary T cell responses to injected SAg are also very transient and even more rapidly aborted than the primary response (7).…”

Section: S Uperantigens (Sag)mentioning

confidence: 99%

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Superantigen-Induced CD4 T Cell Tolerance Mediated by Myeloid Cells and IFN-γ

Cauley

Miller

Yen

et al. 2000

The Journal of Immunology

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We have previously shown that systemic staphylococcal enterotoxin A (SEA) injections cause CD4 T cells in TCR-transgenic mice to become tolerant to subsequent ex vivo restimulation. An active IFN-γ-dependent mechanism of suppression was responsible for the apparent unresponsiveness of the CD4 T cells. In this study, we analyze the response of CD4 T cells isolated throughout the first 10 days of the in vivo response to injected SEA. We show that CD4 T cells isolated at the peak of the in vivo response undergo very little activation-induced cell death after sterile FACS sorting or restimulation in the presence of neutralizing Abs to IFN-γ. We also show that the IFN-γ-dependent tolerance develops soon after SEA injection in the spleens of both normal and TCR-transgenic mice. This suppression is dependent upon myeloid cells from the SEA-treated mice and is optimal when inducible NO synthase activity and reactive oxygen intermediates are both present. The data indicate that IFN-γ, myeloid cells, and a combination of NO and reactive oxygen intermediates all contribute to a common pathway of T cell death that targets activated or responding CD4 T cells. Sorted Gr-1+ cells from SEA-treated mice also directly suppress the response of naive CD4 T cells in mixed cultures, indicating that this tolerance mechanism may play a role in down-regulating other vigorous immune responses.

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Section: Discussionmentioning

confidence: 96%

Section: S Uperantigens (Sag)mentioning

confidence: 99%

Superantigen-Induced CD4 T Cell Tolerance Mediated by Myeloid Cells and IFN-γ

Cauley

Miller

Yen

et al. 2000

The Journal of Immunology

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“…Thus, in the case of a large V␤ family, such as V␤8 receptors, which account for ϳ20% of the murine T cell repertoire, activation with an appropriate superantigen may affect an enormous sector of the total repertoire, far greater than the proportion involved in a given peptidespecific response. Superantigenic stimulation results in a systemic release of proinflammatory cytokines, including IL-1, TNF-␣, TNF␤, and IFN-␥ (8 -11) with rapid expansion of T cells followed by deletion or anergy (12).…”

mentioning

confidence: 99%

The Mechanism of Superantigen-Mediated Toxic Shock: Not a Simple Th1 Cytokine Storm

Faulkner

Cooper

Fantino

et al. 2005

The Journal of Immunology

110

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The profound clinical consequences of Gram-positive toxic shock are hypothesized to stem from excessive Th1 responses to superantigens. We used a new superantigen-sensitive transgenic model to explore the role of TCRαβ T cells in responses to staphylococcal enterotoxin B (SEB) in vitro and in two different in vivo models. The proliferative and cytokine responses of HLA-DR1 spleen cells were 100-fold more sensitive than controls and were entirely dependent on TCRαβ T cells. HLA-DR1 mice showed greater sensitivity in vivo to two doses of SEB with higher mortality and serum cytokines than controls. When d-galactosamine was used as a sensitizing agent with a single dose of SEB, HLA-DR1 mice died of toxic shock whereas controls did not. In this sensitized model of toxic shock there was a biphasic release of cytokines, including TNF-α, at 2 h and before death at 7 h. In both models, mortality and cytokine release at both time points were dependent on TCRαβ T cells. Anti-TNF-α pretreatment was protective against shock whereas anti-IFN γ pretreatment and delayed anti-TNF-α treatment were not. Importantly, anti-TNF-α pretreatment inhibited the early TNF-α response but did not inhibit the later TNF-α burst, to which mortality has previously been attributed. Splenic T cells were shown definitively to be the major source of TNF-α during the acute cytokine response. Our results demonstrate unequivocally that TCRαβ T cells are critical for lethality in toxic shock but it is the early TNF-α response and not the later cytokine surge that mediates lethal shock.

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“…Treatment of mice with strong superantigens such as SEB has been shown to induce AICD of Vb8 þ T cell clones, and thus cause non-responsiveness of the animal's T cells to the superantigen [17]. The extent of non-responsiveness induced by SEB treatment was investigated in the mice with chronic GVHD of 3 weeks duration.…”

Section: Effect Of Treatment With Csa On Antigen-specific Th Cell Nonmentioning

confidence: 99%

Antigen-presenting cells (APC) of mice with chronic graft-versus-host disease (GVHD) cause excessive activation-induced death of T helper cells

Haridas

Kamat

1997

Clinical and Experimental Immunology

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SUMMARYBoth experimental and clinical forms of chronic GVHD have unique immunological features. The affected animals/individuals suffer from autoimmune disorders such as systemic lupus erythematosus (SLE), and yet they are unable to mount a self MHC-restricted T cell response to foreign antigens. Pathogenesis of the latter phenomenon was investigated in an experimental model of chronic GVHD. Chronic GVHD was induced in 8-10-week-old (B6 × C3H)F 1 mice by tail vein injection of 5 × 10 7 spleen cells of C3H parental strain. The recipients, when tested 3 months later, were unable to mount a T helper (Th) cell response to a randomly selected immunogen, a vaccine of 10 8 killed Mycobacterium vaccae. The animals showed evidence of generalized lymphoid hyperplasia, as indicated by GVH index >1 . 34, and also revealed autoantibodies against erythrocytes and dsDNA, indicating establishment of chronic GVHD. However, mice with chronic GVHD of only 3 weeks duration were able to mount the Th cell response to M. vaccae. Three consecutive immunizations of these mice at 1-week intervals, with the same immunogen, resulted in the mice becoming non-responsive to the antigen. All the three responses tested, namely the DTH, lymphoproliferation and the antibody responses, were adversely affected. The non-responsiveness induced was antigen-specific. Mice receiving two immunizations with M. vaccae responded normally to Salmonella enteritidis. Pulse treatment with cyclosporin A 0 . 5 mg/mouse by the i.p. route, on days 0, 1, 2, 3 and 4 at the time of immunization with M. vaccae on day 1, prevented emergence of non-responsiveness. Based on this evidence, it was concluded that repeated activation of T cells of mice with chronic GVHD induces non-responsiveness. Extent of clonal loss due to activationinduced cell death (AICD) caused by i.p. injection with a superantigen Staphylococcal enterotoxin B (SEB) was investigated in F 1 mice with chronic GVHD. I.p. injection of 25 mg/mouse of SEB induced loss of SEB responding clones in both normal F 1 mice and those having chronic GVHD; however, the extent of loss was much greater in the latter. In vitro antigen-specific proliferation of primed splenic T cells of normal F 1 mice was observed to be quite poor when antigen was presented by APC of mice with chronic GVHD of 3 weeks duration. Proliferation profiles of T cells of normal F 1 mice, in response to stimulation with concanavalin A (Con A) or SEB, were studied, using as APC irradiated spleen cells of normal F 1 mice or of F 1 mice with chronic GVHD of 3 weeks duration. With Con A and APC of normal F 1 mice, peak proliferation was observed at 48 h, which remained at the same level up to 72 h and declined thereafter, possibly due to AICD. With SEB and the normal APC, proliferation progressively peaked at 72 h and declined thereafter. With APC of mice with chronic GVHD, the 48 h proliferative responses of both Con A and SEB were comparable to those caused by APC of normal F 1 mice; however, thereafter the responses declined steeply, suggesting gr...

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Peripheral T‐Cell Reactivity to Bacterial Superantigens in vivo: The Response/Anergy Paradox

Cited by 64 publications

References 71 publications

Superantigen-Induced CD4 T Cell Tolerance Mediated by Myeloid Cells and IFN-γ

Superantigen-Induced CD4 T Cell Tolerance Mediated by Myeloid Cells and IFN-γ

The Mechanism of Superantigen-Mediated Toxic Shock: Not a Simple Th1 Cytokine Storm

Antigen-presenting cells (APC) of mice with chronic graft-versus-host disease (GVHD) cause excessive activation-induced death of T helper cells

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