NDLI: Noncore RAG1 regions promote Vß rearrangements and ß T cell development by overcoming inherent inefficiency of Vß recombination signal sequences.

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Noncore RAG1 regions promote Vß rearrangements and ß T cell development by overcoming inherent inefficiency of Vß recombination signal sequences.

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Noncore RAG1 regions promote Vß rearrangements and ß T cell development by overcoming inherent inefficiency of Vß recombination signal sequences.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Horowitz, Julie E. Bassing, Craig H.
Description	Author Affiliation: Horowitz JE ( Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.)
Abstract	The RAG proteins are comprised of core endonuclease domains and noncore regions that modulate endonuclease activity. Mutation or deletion of noncore RAG regions in humans causes immunodeficiency and altered TCR repertoire, and mice expressing core but not full-length Rag1 (Rag1(C/C)) or Rag2 (Rag2(C/C)) exhibit lymphopenia, reflecting impaired V(D)J recombination and lymphocyte development. Rag1(C/C) mice display reduced D-to-J and V-to-DJ rearrangements of TCRß and IgH loci, whereas Rag2(C/C) mice show decreased V-to-DJ rearrangements and altered Vß/VH repertoire. Because Vßs/VHs only recombine to DJ complexes, the Rag1(C/C) phenotype could reflect roles for noncore RAG1 regions in promoting recombination during only the D-to-J step or during both steps. In this study, we demonstrate that a preassembled TCRß gene, but not a preassembled DßJß complex or the prosurvival BCL2 protein, completely rescues ß T cell development in Rag1(C/C) mice. We find that Rag1(C/C) mice exhibit altered Vß utilization in Vß-to-DJß rearrangements, increased usage of 3'J gene segments in V -to-J rearrangements, and abnormal changes in Vß repertoire during ß TCR selection. Inefficient Vß/VH recombination signal sequences (RSSs) have been hypothesized to cause impaired V-to-DJ recombination on the background of a defective recombinase as in core-Rag mice. We show that replacement of the Vß14 RSS with a more efficient RSS increases Vß14 recombination and rescues ß T cell development in Rag1(C/C) mice. Our data indicate that noncore RAG1 regions establish a diverse TCR repertoire by overcoming Vß RSS inefficiency to promote Vß recombination and ß T cell development, and by modulating TCRß and TCR gene segment utilization.
ISSN	00221767
e-ISSN	15506606
DOI	10.4049/jimmunol.1301599
Journal	The Journal of Immunology
Issue Number	4
Volume Number	192
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2014-02-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Homeodomain Proteins Genetics Protein Sorting Signals Receptors, Antigen, T-cell, Alpha-beta V(d)j Recombination Animals Cell Differentiation Immunology Metabolism Immunoglobulin Joining Region Mice Mice, Inbred C57bl Mice, Transgenic Proto-oncogene Proteins C-bcl-2 Biosynthesis T-lymphocytes 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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