Self-awareness: how self-peptide/MHC complexes are essential in the development of T cells.
Mol Immunol
; 55(2): 186-9, 2013 Sep.
Article
en En
| MEDLINE
| ID: mdl-23196128
ABSTRACT
The processing and presentation of self-proteins is essential to develop an effective immune system, with almost all T cells only ever encountering self-peptide/MHC ligands. How positive selection in the thymus occurs with a weak interaction between the TCR and self-pMHC remains unresolved. The recent identification of a naturally occurring positive selecting self-peptide, gp250, for the MCC/I-E(k) specific T cell, AND, has provided some key insights. Despite the weak 3D affinity of the positive selecting AND TCRgp250/I-E(k) interaction, it induces a sustained Ca(2+) flux and Erk signaling. Transcriptional profiling revealed the unique expression of a voltage-gated sodium channel (VGSC) in DP thymocytes. Blocking of this channel with tetrodotoxin inhibited positive selection of AND and polyclonal CD4T cells in vitro. VGSC sh-RNA knockdown inhibited the selection of CD4, but not CD8T cells. Thus, the expression of a VGSC at the DP stage increases the sensitivity of signaling induced by positively selecting ligands, thereby, providing a mechanism by which a weak TCRself-peptide interaction can result in a sustained developmental signal. One enigma regarding positive selection is that AND TCR recognizes gp250 self-peptide with a high degree of specificity, akin to what is seen with foreign antigen. The self-peptide repertoire is significantly smaller than the T cell repertoire, therefore, each self-peptide has to select many unrelated T cells. Other studies have shown that a single peptide/MHC can select a large number of T cells. To reconcile this dichotomy, we propose a model in which positive selection is not simply a live or die process, but that the strength of the interaction between a TCR and the positive selecting ligand is deterministic for the functional activity of the peripheral T cells.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptores de Antígenos de Linfocitos T
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Linfocitos T CD4-Positivos
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Linfocitos T CD8-positivos
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Canales de Sodio Activados por Voltaje
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Complejo Mayor de Histocompatibilidad
Límite:
Humans
Idioma:
En
Revista:
Mol Immunol
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
ENGLAND
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ESCOCIA
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GB
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GREAT BRITAIN
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INGLATERRA
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REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM