title: Self-awareness: how self-peptide/MHC complexes are essential in the development of T cells.
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 TCR:gp250/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 TCR:self-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.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Wan-Lin
authors.initials: WL
authors.lastname: Lo
authors.forename: Paul M
authors.initials: PM
authors.lastname: Allen
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D020869:Gene Expression Profiling; D006801:Humans; D008285:Major Histocompatibility Complex / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013779:Tetrodotoxin / Q000494:pharmacology; D060168:Thymocytes / Q000378:metabolism; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; D013779:Tetrodotoxin