title: Lineage divergence at the first TCR-dependent checkpoint: preferential γδ and impaired αβ T cell development in nonobese diabetic mice.
abstract: 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 cell-autonomous 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.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Ni
authors.initials: N
authors.lastname: Feng
authors.forename: Patricia
authors.initials: P
authors.lastname: Vegh
authors.forename: Ellen V
authors.initials: EV
authors.lastname: Rothenberg
authors.forename: Mary A
authors.initials: MA
authors.lastname: Yui
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000276:immunology; D016694:Gene Rearrangement, delta-Chain T-Cell Antigen Receptor / Q000276:immunology; D015334:Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD / Q000235:genetics / Q000276:immunology*; D018345:Mice, Knockout; D016513:Mice, SCID; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000502:physiology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta