scholarly journals A Role for Fas in Negative Selection of Thymocytes In Vivo

1998 ◽  
Vol 187 (9) ◽  
pp. 1427-1438 ◽  
Author(s):  
Hidehiro Kishimoto ◽  
Charles D. Surh ◽  
Jonathan Sprent
Keyword(s):  
Negative Selection ◽  
Cell Receptor ◽  
Staphylococcal Enterotoxin B ◽  
Thymic Medulla ◽  
Enterotoxin B ◽  
High Doses ◽  
Specific Peptide ◽  
Selection Of

To seek information on the role of Fas in negative selection, we examined subsets of thymocytes from normal neonatal mice versus Fas-deficient lpr/lpr mice injected with graded doses of antigen. In normal mice, injection of 1–100 μg of staphylococcal enterotoxin B (SEB) induced clonal elimination of SEB-reactive Vβ8+ cells at the level of the semi-mature population of HSAhi CD4+ 8− cells found in the thymic medulla; deletion of CD4+ 8+ cells was minimal. SEB injection also caused marked elimination of Vβ8+ HSAhi CD4+ 8− thymocytes in lpr/lpr mice. Paradoxically, however, elimination of these cells in lpr/lpr mice was induced by low-to-moderate doses of SEB (≤1 μg) but not by high doses (100 μg). Similar findings applied when T cell receptor transgenic mice were injected with specific peptide. These findings suggest that clonal elimination of semi-mature medullary T cells is Fas independent at low doses of antigen but Fas dependent at high doses. Previous reports documenting that negative selection is not obviously impaired in lpr/lpr mice could thus reflect that the antigens studied were expressed at only a low level.

scholarly journals Role of the Multiple T Cell Receptor (TCR)-ζ Chain Signaling Motifs in Selection of the T Cell Repertoire

1997 ◽  
Vol 185 (5) ◽  
pp. 893-900 ◽  
Author(s):  
Elizabeth W. Shores ◽  
Tom Tran ◽  
Alexander Grinberg ◽  
Connie L. Sommers ◽  
Howard Shen ◽  
...  
Keyword(s):  
T Cell ◽  
Negative Selection ◽  
Selection Process ◽  
Cell Receptor ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Ligand Interaction ◽  
Competent Self ◽  
Selection Of

Immature thymocytes undergo a selection process within the thymus based on their T cell antigen receptor (TCR) specificity that results either in their maturation into functionally competent, self-MHC–restricted T cells (positive selection) or their deletion (negative selection). The outcome of thymocyte selection is thought to be controlled by signals transduced by the TCR that vary in relation to the avidity of the TCR–ligand interaction. The TCR is composed of four distinct signal transducing subunits (CD3-γ, -δ, -ε, and ζ) that contain either one (CD3-γ, -δ, -ε) or three (-ζ) signaling motifs (ITAMs) within their intracytoplasmic domains. A possible function for multiple TCR ITAMs could be to amplify signals generated by the TCR during selection. To determine the importance of the multiple TCR-ζ chain ITAMs in thymocyte selection, transgenes encoding α/βTCRs with known specificity were bred into mice in which ζ chains lacking one or more ITAMs had been genetically substituted for endogenous ζ. A direct relationship was observed between the number of ζ chain ITAMs within the TCR complex and the efficiency of both positive and negative selection. These results reveal a role for multiple TCR ITAMs in thymocyte selection and identify a function for TCR signal amplification in formation of the T cell repertoire.

scholarly journals Potent Neutralization of Staphylococcal Enterotoxin B In Vivo by Antibodies that Block Binding to the T-Cell Receptor

2019 ◽  
Vol 431 (21) ◽  
pp. 4354-4367 ◽  
Author(s):  
Gang Chen ◽  
Hatice Karauzum ◽  
Hua Long ◽  
Danielle Carranza ◽  
Frederick W. Holtsberg ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Staphylococcal Enterotoxin ◽  
Staphylococcal Enterotoxin B ◽  
Enterotoxin B ◽  
Potent Neutralization

scholarly journals Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla

2008 ◽  
Vol 205 (11) ◽  
pp. 2575-2584 ◽  
Author(s):  
Tom M. McCaughtry ◽  
Troy A. Baldwin ◽  
Matthew S. Wilken ◽  
Kristin A. Hogquist
Keyword(s):  
Epithelial Cells ◽  
Negative Selection ◽  
Cell Receptor ◽  
Clonal Deletion ◽  
Deletion Event ◽  
Thymic Medulla ◽  
Antigen Presenting ◽  
Tcr Activation ◽  
Self Antigen

The thymic medulla is generally held to be a specialized environment for negative selection. However, many self-reactive thymocytes first encounter ubiquitous self-antigens in the cortex. Cortical epithelial cells are vital for positive selection, but whether such cells can also promote negative selection is controversial. We used the HYcd4 model, where T cell receptor for antigen (TCR) expression is appropriately timed and a ubiquitous self-antigen drives clonal deletion in male mice. We demonstrated unambiguously that this deletion event occurs in the thymic cortex. However, the kinetics in vivo indicated that apoptosis was activated asynchronously relative to TCR activation. We found that radioresistant antigen-presenting cells and, specifically, cortical epithelial cells do not efficiently induce apoptosis, although they do cause TCR activation. Rather, thymocytes undergoing clonal deletion were preferentially associated with rare CD11c+ cortical dendritic cells, and elimination of such cells impaired deletion.

scholarly journals The protective role of endogenously synthesized nitric oxide in staphylococcal enterotoxin B-induced shock in mice.

1994 ◽  
Vol 180 (3) ◽  
pp. 1153-1158 ◽  
Author(s):  
S Florquin ◽  
Z Amraoui ◽  
C Dubois ◽  
J Decuyper ◽  
M Goldman
Keyword(s):  
Nitric Oxide ◽  
Intraperitoneal Administration ◽  
Serum Levels ◽  
Staphylococcal Enterotoxin ◽  
Staphylococcal Enterotoxin B ◽  
Protective Effects ◽  
Ifn Gamma ◽  
Enterotoxin B

Nitric oxide (NO) synthesis during experimental endotoxemia has been shown to have both deleterious and beneficial effects. In the present study, we analyzed the in vivo production and the regulatory role of NO in the shock syndrome induced by staphylococcal enterotoxin B (SEB) in mice. First, we found that intraperitoneal administration of 100 micrograms SEB in BALB/c mice induced a massive synthesis of NO as indicated by high serum levels of nitrite (NO2-) and nitrate (NO3-) peaking 16 h after SEB injection. The inhibition of NO2- and NO3- release in mice injected with anti-tumor necrosis factor (TNF) and/or anti-interferon gamma (IFN-gamma) monoclonal antibody (mAb) before SEB challenge revealed that both cytokines were involved in SEB-induced NO overproduction. In vitro experiments indicated that NO synthase (NOS) inhibition by N-nitro-L-arginine methyl ester (L-NAME) enhanced IFN-gamma and TNF production by splenocytes in response to SEB. A similar effect was observed in vivo as treatment of mice with L-NAME resulted in increased IFN-gamma and TNF serum levels 24 h after SEB challenge, together with persistent expression of corresponding cytokine mRNA in spleen. The prolonged production of inflammatory cytokines in mice receiving L-NAME and SEB was associated with a 95% mortality rate within 96 h, whereas all mice survived injections of SEB or L-NAME alone. Both TNF and INF-gamma were responsible for the lethality induced by SEB in L-NAME-treated mice as shown by the protection provided by simultaneous administration of anti-IFN-gamma and anti-TNF mAbs. We conclude the SEB induces NO synthesis in vivo and that endogenous NO has protective effects in this model of T cell-dependent shock by downregulating IFN-gamma and TNF production.

scholarly journals Endogenous Superantigens Shape Response to Exogenous Superantigens

2005 ◽  
Vol 12 (9) ◽  
pp. 1119-1122 ◽  
Author(s):  
Govindarajan Rajagopalan ◽  
Manisha Singh ◽  
Moon M. Sen ◽  
Narayana S. Murali ◽  
Karl A. Nath ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Negative Selection ◽  
Cell Receptor ◽  
Staphylococcal Enterotoxin ◽  
Staphylococcal Enterotoxin B ◽  
Enterotoxin B

ABSTRACT Endogenous superantigen-mediated thymic negative selection resulted in a paucity of mature T cells bearing T-cell receptor (TCR) Vβ8 in the periphery. Consequently, the magnitude of immune response to exogenous superantigen staphylococcal enterotoxin B, which activates TCR Vβ8+ T cells, was significantly reduced and conferred protection from superantigen-induced mortality.

scholarly journals Crucial Role of Jak3 in Negative Selection of Self-reactive T Cells

1997 ◽  
Vol 185 (2) ◽  
pp. 351-356 ◽  
Author(s):  
Kaoru Saijo ◽  
Seung Yong Park ◽  
Yasuo Ishida ◽  
Hisashi Arase ◽  
Takashi Saito
Keyword(s):  
T Cells ◽  
Negative Selection ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Peripheral Tissues ◽  
Activated State ◽  
Peripheral T Cells ◽  
Deficient Mice ◽  
Selection Of

Jak3 mediates growth signals through cytokine receptors such as interleukin-2 (IL-2), IL-4, and IL-7, and its deficiency results in autosomal recessive SCID in mice and humans. In spite of the severely reduced number of lymphocytes in Jak3-deficient mice, the differentiation profile of thymocytes was normal and mature T cells accumulated in the periphery with age. However, we found that self-reactive T cells were not deleted in the thymus and the peripheral tissues in Jak3-deficient mice. All peripheral T cells were in the activation state and thus were unable to be activated further, as demonstrated by the failure of eliciting Ca2+ response upon T cell receptor (TCR) stimulation. From the analysis of TCR-transgenic Jak3-deficient mice, only self-reactive T cells appeared to be in the activated state and anergic. These findings demonstrate a crucial function of Jak3 in the negative selection of autoreactive T cells and the maintenance of functional peripheral T cells.

scholarly journals Role of the H-2 complex in induction of T helper cells in vivo. II Negative selection of discrete subgroups of T cells restricted by I-A and I-A/E determinants.

1981 ◽  
Vol 153 (4) ◽  
pp. 823-831 ◽  
Author(s):  
J Sprent ◽  
B Alpert
Keyword(s):  
T Cells ◽  
T Helper Cells ◽  
Negative Selection ◽  
T Helper ◽  
Discrete Subgroups ◽  
Hybrid Molecules ◽  
Donor T Cells ◽  
Selection Of

Previous studies have shown that negative selection of T cells to sheep erythrocytes (SRC) after adoptive transfer to irradiated mice requires a sharing of H-2 determinants between the donor T cells and the selection hosts. This paper examines which part of the H-2 complex controls selection. The results show that, in the case of T cells of the H-2k haplotype, complete selection occurs with donor host matching limited to the I-A through I-E subregions of the H-2 complex. Selection to SRC was partial in I-A compatible, I-E incompatible hosts, minimal or not detectable in I-A incompatible, I-E compatible hosts, but near-complete in hosts matched at both the I-A and I-E subregions. Consecutive selection in hosts matched solely at (a) the I-A subregion and (b) the I-E subregion led to incomplete selection. From these and other findings it is argued that H-2k T cells comprise a mixture of T cells restricted by I-A and I-A/E hybrid molecules.

The role of the T cell receptor in positive and negative selection of developing T cells

Science ◽  
1990 ◽  
Vol 248 (4961) ◽  
pp. 1335-1341 ◽  
Author(s):  
M Blackman ◽  
J Kappler ◽  
P Marrack
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Negative Selection ◽  
Cell Receptor ◽  
Selection Of
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