| First Author | Feng N | Year | 2011 |
| Journal | J Immunol | Volume | 186 |
| Issue | 2 | Pages | 826-37 |
| PubMed ID | 21148803 | Mgi Jnum | J:168778 |
| Mgi Id | MGI:4938224 | Doi | 10.4049/jimmunol.1002630 |
| Citation | Feng N, et al. (2011) Lineage divergence at the first TCR-dependent checkpoint: preferential gammadelta and impaired alphabeta T cell development in nonobese diabetic mice. J Immunol 186(2):826-37 |
| abstractText | The first TCR-dependent checkpoint in the thymus determines alphabeta versus gammadelta 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 alphabeta T cells, whereas gammadelta T cell development from bipotent precursors was enhanced. Limiting dilution and single-cell experiments show that the divergent effects on alphabeta and gammadelta T cell development did not spring from biased lineage choice but from increased proliferation of gammadelta T cells and impaired accumulation of alphabeta T lineage double-positive cells. In vivo, NOD early T cell subsets in the thymus also show characteristics indicative of defective beta-selection, and peripheral alphabeta T cells are poorly established in mixed bone marrow chimeras, contrasting with strong gammadelta 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. |
