scholarly journals Induction of unresponsiveness and impaired T cell expansion by staphylococcal enterotoxin B in CD28-deficient mice.

1996 ◽  
Vol 183 (6) ◽  
pp. 2481-2488 ◽  
Author(s):  
H W Mittrücker ◽  
A Shahinian ◽  
D Bouchard ◽  
T M Kündig ◽  
T W Mak
Keyword(s):  
T Cells ◽  
T Cell ◽  
Staphylococcal Enterotoxin ◽  
Staphylococcal Enterotoxin B ◽  
Rapid Induction ◽  
Cd28 Costimulation ◽  
Enterotoxin B ◽  
Deficient Mice

We used CD28-deficient mice to analyze the importance of CD28 costimulation for the response against Staphylococcal enterotoxin B (SEB) in vivo. CD28 was necessary for the strong expansion of V beta 8+ T cells, but not for deletion. The lack of expansion was not due to a failure of SEB to activate V beta 8+ T cells, as V beta 8+ T cells from both CD28-/- and CD28+/+ mice showed similar phenotypic changes within the first 24 h after SEB injection and cell cycle analysis showed that an equal percentage of V beta 8+ T cells started to proliferate. However, the phenotype and the state of proliferation of V beta 8+ T cells was different at later time points. Furthermore, in CD28-/- mice injection with SEB led to rapid induction of unresponsiveness in SEB responsive T cells, indicated by a drastic reduction of proliferation after secondary SEB stimulation in vitro. Unresponsiveness could also be demonstrated in vivo, as CD28-/- mice produced only marginal amounts of TNF alpha after rechallenge with SEB. In addition CD28-/- mice were protected against a lethal toxic shock induced by a second injection with SEB. Our results indicate that CD28 costimulation is crucial for the T cell-mediated toxicity of SEB and demonstrate that T cell stimulation in the absence of CD28 costimulation induces unresponsiveness in vivo.

scholarly journals In vivo induction of anergy in peripheral V beta 8+ T cells by staphylococcal enterotoxin B.

1990 ◽  
Vol 172 (4) ◽  
pp. 1091-1100 ◽  
Author(s):  
B L Rellahan ◽  
L A Jones ◽  
A M Kruisbeek ◽  
A M Fry ◽  
L A Matis
Keyword(s):  
T Cells ◽  
T Cell ◽  
No Reduction ◽  
Interleukin 2 ◽  
Staphylococcal Enterotoxin ◽  
Staphylococcal Enterotoxin B ◽  
Clonal Deletion ◽  
Enterotoxin B

We have developed a model of peripheral in vivo T cell tolerance that is induced by administration of the protein superantigen staphylococcal enterotoxin B (SEB). Rather than activating V beta 8+ T cells, in vivo administration of SEB induced in them a profound state of anergy. This was shown by their failure to proliferate to subsequent in vitro restimulation with SEB or to anti-V beta 8 antibodies. This unresponsiveness was V beta 8 specific since T cells from SEB-immunized mice responded normally to other antigens. 8 d after SEB administration, there was no reduction in the number of V beta 8+ T cells or in the intensity of V beta 8 T cell receptor (TCR) expression. Although a portion of the V beta 8+ T cells from SEB-primed mice were able to express interleukin 2 receptors (IL-2Rs), they failed to proliferate in response to exogenous IL-2, indicating they were defective in their IL-2 responsiveness. 2-4 wk after SEB administration, there was a reduction of approximately 50% in the number of V beta 8+ cells in immunized compared with control animals. There was, however, no reduction in the level of TCR expression on the remaining V beta 8+ cells. These data demonstrate that proteins that activate T cells in vitro in a V beta-specific manner can induce a state of anergy in peripheral T cells in vivo and may possibly further mediate clonal deletion in a portion of the tolerized cells.

scholarly journals Mycobacterium bovis BCG-Infected Mice Are More Susceptible to Staphylococcal Enterotoxin B-Mediated Toxic Shock than Uninfected Mice despite Reduced In Vitro Splenocyte Responses to Superantigens

2002 ◽  
Vol 70 (8) ◽  
pp. 4148-4157 ◽  
Author(s):  
João A. Pedras-Vasconcelos ◽  
Yvan Chapdelaine ◽  
Renu Dudani ◽  
Henk van Faassen ◽  
Dean K. Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Staphylococcal Enterotoxin ◽  
Staphylococcal Enterotoxin B ◽  
Strong Type ◽  
Ifn Γ ◽  
Enterotoxin B

ABSTRACT Type 1 T-cell responses against intracellular pathogens play a crucial role in mediating protection. We examined whether the induction of a strong type 1 T-cell response during a chronic bacterial infection influences responses to superantigens capable of inducing acute shock. Intravenous infection of mice with Mycobacterium bovis BCG appeared to induce a progressive anergy towards staphylococcal enterotoxin B (SEB) and towards antigen preparation of BCG (BCG-Ag) itself, based on diminished gamma interferon (IFN-γ) production by SEB- and BCG-Ag-stimulated splenocytes from infected mice. In contrast to these in vitro results, injection of SEB into BCG-infected mice led to a dramatic increase in the serum IFN-γ levels and the death of infected but not of control mice. In vitro hyporesponsiveness towards SEB and BCG-Ag occurred only with unfractionated splenocyte cultures, as purified T cells from infected mice produced higher levels of IFN-γ. Hyporesponsiveness towards SEB and BCG-Ag in unfractionated splenocyte cultures was not due to suppressive antigen-presenting cells (APCs), as APCs from infected mice stimulated higher levels of IFN-γ from purified T cells. The diminished IFN-γ levels observed with bulk splenocytes appear to be due to changes in the T-cell-to-APC ratio that result in a decreased proportion of T cells, coupled to reduced proliferative responses and an increased susceptibility of effector T cells to activation-induced cell death in vitro. Our results indicate that the reported phenomena of T-cell anergy during mycobacterial infection may be an in vitro consequence of the development of a strong type 1 response in vivo.

scholarly journals CD28 Costimulation Is Required for In Vivo Induction of Peripheral Tolerance in CD8 T Cells

2002 ◽  
Vol 197 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Melanie S. Vacchio ◽  
Richard J. Hodes
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tolerance Induction ◽  
Peripheral Tolerance ◽  
Cd8 Cells ◽  
Costimulatory Signal ◽  
Cd28 Costimulation

Whereas ligation of CD28 is known to provide a critical costimulatory signal for activation of CD4 T cells, the requirement for CD28 as a costimulatory signal during activation of CD8 cells is less well defined. Even less is known about the involvement of CD28 signals during peripheral tolerance induction in CD8 T cells. In this study, comparison of T cell responses from CD28-deficient and CD28 wild-type H-Y–specific T cell receptor transgenic mice reveals that CD8 cells can proliferate, secrete cytokines, and generate cytotoxic T lymphocytes efficiently in the absence of CD28 costimulation in vitro. Surprisingly, using pregnancy as a model to study the H-Y–specific response of maternal T cells in the presence or absence of CD28 costimulation in vivo, it was found that peripheral tolerance does not occur in CD28KO pregnants in contrast to the partial clonal deletion and hyporesponsiveness of remaining T cells observed in CD28WT pregnants. These data demonstrate for the first time that CD28 is critical for tolerance induction of CD8 T cells, contrasting markedly with CD28 independence of in vitro activation, and suggest that the role of CD28/B7 interactions in peripheral tolerance of CD8 T cells may differ significantly from that of CD4 T cells.

scholarly journals Memory T cells are anergic to the superantigen staphylococcal enterotoxin B.

1992 ◽  
Vol 176 (2) ◽  
pp. 575-579 ◽  
Author(s):  
W T Lee ◽  
E S Vitetta
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Immune Deficiency Syndrome ◽  
Deficiency Syndrome ◽  
Staphylococcal Enterotoxin ◽  
Peripheral Tolerance ◽  
Staphylococcal Enterotoxin B ◽  
Enterotoxin B

We have used staphylococcal enterotoxin B (SEB) to study the role of naive and memory T cells in the induction of peripheral tolerance. After administration of SEB to mice, the numbers of naive and memory T cells increase, as does the proportion of memory T cells, which are unresponsive to further stimulation with SEB in vitro. In addition, memory T cells generated in response to conventional antigen, which proliferate and provide help to B cells in the presence of the conventional antigen, fail to respond to superantigen. Hence, memory T cells, in general, are anergized by SEB. These results suggest that SEB-induced activation and anergy reflect the combined responses of naive and memory T cells. The differential activation vs. anergy of naive and memory T cells by superantigen may be related to cytokine production and may play an important role in the etiology of autoimmune diseases or immunodeficiency diseases such as acquired immune deficiency syndrome.

scholarly journals Selective anergy of V beta 8+,CD4+ T cells in Staphylococcus enterotoxin B-primed mice.

1990 ◽  
Vol 172 (4) ◽  
pp. 1065-1070 ◽  
Author(s):  
Y Kawabe ◽  
A Ochi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
T Cell Anergy ◽  
Specific Cytotoxicity ◽  
Enterotoxin B ◽  
Staphylococcus Enterotoxin B

The cellular basis of the in vitro and in vivo T cell responses to Staphylococcus enterotoxin B (SEB) has been investigated. The proliferation and cytotoxicity of V beta 8.1,2+,CD4+ and CD8+ T cells were observed in in vitro response to SEB. In primary cytotoxicity assays, CD4+ T cells from control spleens were more active than their CD8+ counterparts, however, in cells derived from SEB-primed mice, CD8+ T cells were dominant in SEB-specific cytotoxicity. In vivo priming with SEB abrogated the response of V beta 8.1,2+,CD4+ T cells despite the fact that these cells exist in significant number. This SEB-specific anergy occurred only in V beta 8.1,2+,CD4+ T cells but not in CD8+ T cells. These findings indicate that the requirement for the induction of antigen-specific anergy is different between CD4+ and CD8+ T cells in post-thymic tolerance, and the existence of coanergic signals for the induction of T cell anergy is suggested.

Functional and Molecular Analysis of Maturation of Thymocytes in Bcl10 or Malt1 Deficient Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3323-3323
Author(s):  
Philipp J. Jost ◽  
Uta Ferch ◽  
Stephanie Weiss ◽  
Stephanie Leeder ◽  
Olaf Gross ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Animals ◽  
Adaptor Proteins ◽  
Cell Receptor ◽  
Single Positive ◽  
T Cell Selection ◽  
Deficient Mice

Abstract Development of immature T cells in the thymus requires signals through the clonotypic T cell receptor (TCR). Thymocytes expressing a functionally inactive or autoreactive TCR are deleted via apoptosis (negative selection). Thymocytes expressing a functionally active but not autoreactive TCR are selected through inhibition of cell death (positive selection). Deregulation of this process is likely to result in autoimmunity or lymphomagenesis of T cells. The intracellular mechanisms by which the balance between TCR-dependent survival and apoptosis are regulated are largely unknown. A central regulator of survival and apoptosis in the immune system is the transcription factor NF-κB. Activation of NF-κB in mature T-cells requires the adaptor proteins Bcl10 and Malt1. Using gene-targeted mice deficient for Bcl10 or Malt1, we show that Bcl10 and Malt1 are also required for TCR-induced NF-κB activation in immature T cells. Furthermore, to elucidate the process of T cell selection within the thymus, we have crossed Bcl10 or Malt1 deficient mice into mice with genetic backgrounds expressing defined TCR transgenes. Using specific peptide agonists of these TCR transgenes, we show that neither in vivo nor in vitro development into single positive (SP) CD4 or CD8 positive T cells is altered in Bcl10 or Malt1 deficient mice. Absolute numbers and ratio of SP T cells found within the thymus or in peripheral lymphnodes of transgenic animals are normal. These findings indicate that Bcl10 and Malt1 activate NF-κB in thymocytes but are dispensable for maturation of immature T cells in this model system.

scholarly journals Strong CD28 costimulation suppresses induction of regulatory T cells from naive precursors through Lck signaling

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3096-3103 ◽  
Author(s):  
Kenrick Semple ◽  
Antony Nguyen ◽  
Yu Yu ◽  
Honglin Wang ◽  
Claudio Anasetti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Protein Tyrosine Kinase ◽  
Cell Receptor ◽  
Specific Protein ◽  
Cell Immunity ◽  
Cd28 Costimulation

Abstract CD28 costimulation is required for the generation of naturally derived regulatory T cells (nTregs) in the thymus through lymphocyte-specific protein tyrosine kinase (Lck) signaling. However, it is not clear how CD28 costimulation regulates the generation of induced Tregs (iTregs) from naive CD4 T-cell precursors in the periphery. To address this question, we induced iTregs (CD25+Foxp3+) from naive CD4 T cells (CD25−Foxp3−) by T-cell receptor stimulation with additional transforming growth factorβ (TGFβ) in vitro, and found that the generation of iTregs was inversely related to the level of CD28 costimulation independently of IL-2. Using a series of transgenic mice on a CD28-deficient background that bears wild-type or mutated CD28 in its cytosolic tail that is incapable of binding to Lck, phosphoinositide 3-kinase (PI3K), or IL-2–inducible T-cell kinase (Itk), we found that CD28-mediated Lck signaling plays an essential role in the suppression of iTreg generation under strong CD28 costimulation. Furthermore, we demonstrate that T cells with the CD28 receptor incapable of activating Lck were prone to iTreg induction in vivo, which contributed to their reduced ability to cause graft-versus-host disease. These findings reveal a novel mechanistic insight into how CD28 costimulation negatively regulates the generation of iTregs, and provide a rationale for promoting T-cell immunity or tolerance by regulating Tregs through targeting CD28 signaling.

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