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* Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
Department of Immunology, University of Pittsburgh School of Medicine and
University of Pittsburgh Cancer Institute and Department of Pathology, Hillman Cancer Center, Pittsburgh, PA 15213;
Department of Pediatrics and Immunology, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh Rangos Research Center, Pittsburgh, PA 15213;
¶ Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912; and
|| Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655
A subset of NK cells bears incomplete V(D)J rearrangements, but neither the consequence to cell activities nor the precise developmental stages in which recombination occurs is known. These are important issues, as recombination errors cause cancers of the B and T lineages. Using transgenic recombination reporter mice to examine NK cell dynamics in vivo, we show that recombination+ NK cells have distinct developmental patterns in the BM, including reduced homeostatic proliferation and diminished Stat5 phosphorylation. In the periphery, both recombination+ and recombination– NK cells mediate robust functional responses including IFN-
production, cytolysis, and tumor homing, suggesting that NK cells with distinct developmental histories can be found together in the periphery. We also show that V(D)J rearrangement marks both human cytolytic (CD56dim) and immunoregulatory (CD56bright) populations, demonstrating the distribution of permanent DNA rearrangements across major NK cell subsets in man. Finally, direct quantification of rag transcripts throughout NK cell differentiation in both mouse and man establishes the specific developmental stages that are susceptible to V(D)J rearrangement. Together, these data demonstrate that multipotent progenitors rather than lineage-specified NK progenitors are targets of V(D)J recombination and that NK cells bearing the relics of earlier V(D)J rearrangements have different developmental dynamics but robust biological capabilities in vivo.
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1 This work was supported by National Institutes of Health Grant R03AR054529, the Elsa U. Pardee Foundation, and the U.S. Immune Deficiency Network (to L. Borghesi); National Institutes of Health, National Cancer Institute Grant R01CA104560 (to P.B.); National Institutes of Health Grant R01AI58181 (to L. Brossay); National Institutes of Health Grant R01DE14775 (to N.V.); National Institutes of Health Grant R01AI043534 (to R.G.); the University of Pittsburgh Cancer and Aging Program (P20-CA103730) and National Institutes of Health Grant R01AG023379 (to A.V.).
2 Address correspondence and reprint requests to Dr. Lisa Borghesi, University of Pittsburgh School of Medicine, E1011 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261. E-mail address: borghesi{at}pitt.edu
3 Abbreviations used in this paper: V(D)J, variable diversity joining; IgH, Ig H chain; BM, bone marrow; BEX, blue excited; CLP, common lymphoid progenitor; DAPI, 4',6'-diamidino-2-phenylindole; pNK, NK precursor; SLT, secondary lymphoid tissue; VEX, violet light excited.
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