NDLI: The ability to rearrange dual TCRs enhances positive selection, leading to increased Allo- and Autoreactive T cell repertoires.

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The ability to rearrange dual TCRs enhances positive selection, leading to increased Allo- and Autoreactive T cell repertoires.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Solomon, Benjamin Hsieh, Chyi-Song Morris, Gerald P. Ni, Peggy P. Allen, Paul M.
Description	Author Affiliation: Ni PP ( Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110); Solomon B ( Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110); Hsieh CS ( Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110); Allen PM ( Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110); Morris GP ( Department of Pathology, University of California, San Diego, La Jolla, CA 92093 gpmorris@ucsd.edu.)
Abstract	Thymic selection is designed to ensure TCR reactivity to foreign Ags presented by self-MHC while minimizing reactivity to self-Ags. We hypothesized that the repertoire of T cells with unwanted specificities such as alloreactivity or autoreactivity are a consequence of simultaneous rearrangement of both TCR loci. We hypothesized that this process helps maximize production of thymocytes capable of successfully completing thymic selection, but results in secondary TCRs that escape stringent selection. In T cells expressing two TCRs, one TCR can mediate positive selection and mask secondary TCR from negative selection. Examination of mice heterozygous for TRAC (TCR (+/-)), capable of only one functional TCR rearrangement, demonstrated a defect in generating mature T cells attributable to decreased positive selection. Elimination of secondary TCRs did not broadly alter the peripheral T cell compartment, though deep sequencing of TCR repertoires of dual TCR T cells and TCR (+/-) T cells demonstrated unique TCRs in the presence of secondary rearrangements. The functional impact of secondary TCRs on the naive peripheral repertoire was evidenced by reduced frequencies of T cells responding to autoantigen and alloantigen peptide-MHC tetramers in TCR (+/-) mice. T cell populations with secondary TCRs had significantly increased ability to respond to altered peptide ligands related to their allogeneic ligand as compared with TCR (+/-) cells, suggesting increased breadth in peptide recognition may be a mechanism for their reactivity. Our results imply that the role of secondary TCRs in forming the T cell repertoire is perhaps more significant than what has been assumed.
ISSN	00221767
e-ISSN	15506606
DOI	10.4049/jimmunol.1400532
Journal	The Journal of Immunology
Issue Number	4
Volume Number	193
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2014-08-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Cd4-positive T-lymphocytes Immunology Cd8-positive T-lymphocytes Receptors, Antigen, T-cell, Alpha-beta Genetics Thymocytes Amino Acid Sequence Animals Autoantigens Cho Cells Cell Differentiation Cells, Cultured Cricetulus Genetic Variation Graft Vs Host Disease Mice Mice, Inbred C57bl Mice, Transgenic T-lymphocyte Subsets Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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The Ability to Rearrange Dual TCRs Enhances Positive Selection, Leading to Increased Allo- and Autoreactive T Cell Repertoires

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The ability to rearrange dual TCRs enhances positive selection, leading to increased Allo- and Autoreactive T cell repertoires.

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The ability to rearrange dual TCRs enhances positive selection, leading to increased Allo- and Autoreactive T cell repertoires.