Feng, Ni and Vegh, Patricia and Rothenberg, Ellen V. and Yui, Mary A. (2011) Lineage Divergence at the First TCR-Dependent Checkpoint: Preferential γδ and Impaired αβ T Cell Development in Nonobese Diabetic Mice. Journal of Immunology, 186 (2). pp. 826-837. ISSN 0022-1767 http://resolver.caltech.edu/CaltechAUTHORS:20110316-093514596
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The first TCR-dependent checkpoint in the thymus determines αβ versus γδ T lineage fate and sets the stage for later T cell differentiation decisions. We had previously shown that early T cells in NOD mice that are unable to rearrange a TCR exhibit a defect in checkpoint enforcement at this stage. To determine if T cell progenitors from wild-type NOD mice also exhibit cellautonomous defects in development, we investigated their differentiation in the Notch-ligand–presenting OP9-DL1 coculture system, as well as by analysis of T cell development in vivo. Cultured CD4 and CD8 double-negative cells from NOD mice exhibited major defects in the generation of CD4 and CD8 double-positive αβ T cells, whereas γδ T cell development from bipotent precursors was enhanced. Limiting dilution and single-cell experiments show that the divergent effects on αβ and γδ T cell development did not spring from biased lineage choice but from increased proliferation of γδ T cells and impaired accumulation of αβ T lineage double-positive cells. In vivo, NOD early T cell subsets in the thymus also show characteristics indicative of defective β-selection, and peripheral αβ T cells are poorly established in mixed bone marrow chimeras, contrasting with strong γδ T as well as B cell repopulation. Thus, NOD T cell precursors reveal divergent, lineage-specific differentiation abnormalities in vitro and in vivo from the first TCR-dependent developmental choice point, which may have consequences for subsequent lineage decisions and effector functions.
|Additional Information:||© 2011 American Association of Immunologists. Received for publication August 2, 2010. Accepted for publication November 9, 2010. We thank J. C. Zuñiga-Pflücker for generously providing OP9-DL1 and OP9-DL4 cells for these experiments, Rochelle Diamond, Stephanie Adams, Diane Perez, and Pat Koen from the Caltech Cell Sorting Facility for cell sorting, Natasha Bouey, Robert Butler, Ruben Bayon, and Beth Olsen for excellent animal care, Marion Duprilot for preliminary gene expression data, and Tom Taghon (University of Ghent, Belgium) and members of the Rothenberg laboratory, especially Rochelle Diamond, for helpful suggestions. This work was supported by grants from the Juvenile Diabetes Research Foundation International, the National Institutes of Health (AI64590 to M.A.Y.), the Al Sherman Foundation, the Louis A. Garfinkle Memorial Laboratory Fund, the Vanguard Charitable Endowment for Diabetes in Memory of Bently Pritsker, and the Albert Billings Ruddock Professorship (to E.V.R.).|
|Official Citation:||Lineage Divergence at the First TCR-Dependent Checkpoint: Preferential γδ and Impaired αβ T Cell Development in Nonobese Diabetic Mice Ni Feng, Patricia Vegh, Ellen V. Rothenberg, and Mary A. Yui J Immunol 2011 186:826-837; published ahead of print December 10, 2010, doi:10.4049/jimmunol.1002630|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Ruth Sustaita|
|Deposited On:||17 Mar 2011 19:30|
|Last Modified:||17 Mar 2011 19:30|
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