The activation threshold of CD4+ T cells is defined by TCR/peptide-MHC class II interactions in the thymic medulla.
J Immunol
; 183(9): 5554-62, 2009 Nov 01.
Article
em En
| MEDLINE
| ID: mdl-19843939
ABSTRACT
Immature thymocytes that are positively selected based upon their response to self-peptide-MHC complexes develop into mature T cells that are not overtly reactive to those same complexes. Developmental tuning is the active process through which TCR-associated signaling pathways of single-positive thymocytes are attenuated to respond appropriately to the peptide-MHC molecules that will be encountered in the periphery. In this study, we explore the mechanisms that regulate the tuning of CD4(+) single-positive T cells to MHC class II encountered in the thymic medulla. Experiments with murine BM chimeras demonstrate that tuning can be mediated by MHC class II expressed by either thymic medullary epithelial cells or thymic dendritic cells. Tuning does not require the engagement of CD4 by MHC class II on stromal cells. Rather, it is mediated by interactions between MHC class II and the TCR. To understand the molecular changes that distinguish immature hyperactive T cells from tuned mature CD4(+) T cells, we compared their responses to TCR stimulation. The altered response of mature CD4 single-positive thymocytes is characterized by the inhibition of ERK activation by low-affinity self-ligands and increased expression of the inhibitory tyrosine phosphatase SHP-1. Thus, persistent TCR engagement by peptide-MHC class II on thymic medullary stroma inhibits reactivity to self-Ags and prevents autoreactivity in the mature repertoire.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Timo
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Ativação Linfocitária
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Receptores de Antígenos de Linfócitos T
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Linfócitos T CD4-Positivos
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Antígenos de Histocompatibilidade Classe II
Limite:
Animals
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos