Antigen Analogs/MHC Complexes as Specific T Cell Receptor Antagonists

Sette, Alessandro; Alexander, Jeff; Ruppert, Jörg; Snoke, Ken; Franco, Alessandra; Ishioka, Glenn; Grey, Howard M.

doi:10.1146/annurev.iy.12.040194.002213

Cited by 187 publications

(72 citation statements)

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“…Supporting this contention, de Carvalho Nicacio et al found MHC-specific differences in proliferation magnitude to recombinant Puumala virus N-Ag in inbred strains of laboratory house mice (48). In addition, some viral peptides are antagonistic to T cell responses, such that they can impact effector T cell maturation (53)(54)(55). Such antagonism can lead to regulatory T cell activation and bystander suppression of an inflammatory immune response (56).…”

Section: Discussionmentioning

confidence: 98%

Regulatory T cell-like responses in deer mice persistently infected with Sin Nombre virus

Schountz

Prescott²,

Cogswell³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

107

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Hantavirus cardiopulmonary syndrome is a zoonotic illness associated with a systemic inflammatory immune response, capillary leak, noncardiogenic pulmonary edema, and shock in humans. Cytokines, including TNF, IFN-␥, and lymphotoxin, are thought to contribute to its pathogenesis. In contrast, infected rodent reservoirs of hantaviruses experience few or no pathologic changes and the host rodent can remain persistently infected for life. Generally, it is unknown why such dichotomous immune responses occur between humans and reservoir hosts. Thus, we examined CD4 ؉ T cell responses from one such reservoir, the deer mouse (Peromy-

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Section: Discussionmentioning

confidence: 98%

Regulatory T cell-like responses in deer mice persistently infected with Sin Nombre virus

Schountz

Prescott²,

Cogswell³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

107

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“…The formation of such complexes has been observed for a variety of proteins and, in some cases, is essential for normal function (23). For instance, oligomerization of the T-cell receptor after interaction with antigen bound to major histocompatability complex is thought to be a necessary event for downstream signaling and immunosurveillance (27,28). Within the field of AD-related research, the N-and C-terminal fragments of presenilin 1 have been shown to be components of a high molecular weight complex containing ␤-catenin that has been implicated in apoptosis (29 -32).…”

Section: Discussionmentioning

confidence: 99%

Maturation and Endosomal Targeting of β-Site Amyloid Precursor Protein-cleaving Enzyme

Huse¹,

Pijak²,

Leslie³

et al. 2000

Journal of Biological Chemistry

385

406

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The amyloidogenic A␤ peptide is liberated from the amyloid precursor protein (APP) by two proteolytic activities, ␤-secretase and ␥-secretase. Recently, a type I membrane protein termed BACE (␤-site APP cleaving enzyme) with characteristics of an aspartyl protease has been identified as the ␤-secretase. We undertook a series of biochemical and morphological investigations designed to characterize the basic properties of this protein. Initial studies indicated that BACE undergoes Nlinked glycosylation at three of four potential sites. Metabolic pulse-chase experiments revealed that after core glycosylation, BACE is rapidly and efficiently transported to the Golgi apparatus and distal secretory pathway. BACE was also found to be quite stable, being turned over with a t1 ⁄2 of ϳ16 h. Retention of BACE in the endoplasmic reticulum by introduction of a C-terminal dilysine motif prevented complex carbohydrate processing and demonstrated that propeptide cleavage occurs after exit from this organelle. BACE exhibited intramolecular disulfide bonding but did not form oligomeric structures by standard SDS-polyacrylamide gel electrophoresis analysis and sedimented as a monomer in sucrose velocity gradients. Immunofluorescence studies showed a largely vesicular staining pattern for BACE that colocalized well with endosomal, but not lysosomal, markers. Measurable levels of BACE were also detected on the plasma membrane by both immunostaining and cell surface biotinylation, and cycling of the protein between the cell membrane and the endosomes was documented. A cytoplasmic dileucine motif was found to be necessary for normal targeting of BACE to the endosomal system and accumulation of the protein in this intracellular site.

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“…The argument against the classical model of competitive inhibition of agonist binding to the receptor has been the fact that there are more TCRs than there are agonist and antagonist-MHC complexes, thereby making it impossible to saturate the TCRs of a cell with antagonist peptide (14,31). However, there are two considerations that mitigate this conclusion.…”

Section: Discussionmentioning

confidence: 99%

“…These changes in TCR affinity for an epitope are typically accomplished by a single conservative amino acid substitution at a TCR contact site. The initial reports that such altered peptide ligands (APL) 3 could strongly affect the outcome of TCR engagement with peptide-MHC complexes demonstrated partial agonist activity (cytokine production in the absence of proliferation) (12) or antagonist activity whereby stimulation of T cells by agonist could be inhibited by the addition of certain APLs to cultures containing Ag-pulsed APCs and T cells (13,14). The mechanism by which inhibition of T cell activation is accomplished by such antagonist APLs remains unresolved.…”

Section: Study Of the Mechanism Of Tcr Antagonism Using Dual-tcr-exprmentioning

confidence: 99%

Study of the Mechanism of TCR Antagonism Using Dual-TCR-Expressing T Cells

Yang

Grey

2003

The Journal of Immunology

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The mechanism of action of TCR antagonists is incompletely understood. T cells expressing two distinct TCRs have been used to test competition for TCR occupancy as a potential mechanism. Previous studies with CD4 T cells showed that an antagonist for one TCR inhibited the response to the other TCR (cross-antagonism), whereas studies with CD8 cells failed to demonstrate cross-antagonism. To determine whether CD4 and CD8 cells were intrinsically different or whether the differences were the result of the use of different effector assays, we studied both CD4 and CD8 dual-TCR-expressing T cells. In the CD4 system, consistent with previous reports, cross-antagonism of proliferation was observed. In the CD8 system, cross-antagonism was observed using proliferation as readout but not when target cell cytolysis was used. These results suggest that different mechanisms may be involved in the inhibition of proliferation and inhibition of cytotoxic effector function, the latter only involving competition for TCR occupancy. Inhibition of proliferation appears to be more complex and other mechanisms such as sequestration of signaling molecules or negative signaling may be involved. The fact that 10- to 20-fold more antagonist was needed to achieve cross-antagonism compared with inhibition of the cognate TCR is consistent with the hypothesis that competition for TCR occupancy is also a major, albeit not sole, mechanism of antagonism of the proliferative responses of CD4 and CD8 cells.

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Antigen Analogs/MHC Complexes as Specific T Cell Receptor Antagonists

Cited by 187 publications

References 0 publications

Regulatory T cell-like responses in deer mice persistently infected with Sin Nombre virus

Regulatory T cell-like responses in deer mice persistently infected with Sin Nombre virus

Maturation and Endosomal Targeting of β-Site Amyloid Precursor Protein-cleaving Enzyme

Study of the Mechanism of TCR Antagonism Using Dual-TCR-Expressing T Cells

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