Biomedical subjects

Aryeh Warmflash

Publications and source records attributed to Aryeh Warmflash.

3 recordsLinked to original sources

PubMed2006

A model for TCR gene segment use.

The TCR alpha-chain is assembled by somatic recombination of variable (V) and joining (J) gene segments at the CD4+ CD8+ stage of development. In this study, we present the first analytical model for deletional rearrangement and show that it is consistent with almost all available data on Valpha Jalpha use in mice and humans. A key feature of the model is that both "local" and "express service" models of rearrangement can be obtained by varying a single parameter that describes the number of gene segments accessible at a time. We find that the window is much larger for Valpha segments than Jalpha segments, which reconciles seemingly conflicting data for the former. Implications for the properties of the repertoire as a whole and experiments that seek to probe them are discussed. Special considerations for allelic inclusion are treated in the Appendices.

Alleles↗

PubMed2006

Multilineage transcriptional priming and determination of alternate hematopoietic cell fates.

Hematopoietic stem cells and their progenitors exhibit multilineage patterns of gene expression. Molecular mechanisms underlying the generation and refinement of these patterns during cell fate determination remain unexplored because of the absence of suitable experimental systems. Using PU.1(-/-) progenitors, we demonstrate that at subthreshold levels, this Ets transcription factor regulates a mixed pattern (macrophage/neutrophil) of gene expression within individual myeloid progenitors. Increased PU.1 levels refine the pattern and promote macrophage differentiation by modulating a novel regulatory circuit comprised of counter antagonistic repressors, Egr-1,2/Nab-2 and Gfi-1. Egr-1 and Egr-2 function redundantly to activate macrophage genes and to repress the neutrophil program. These results are used to assemble and mathematically model a gene regulatory network that exhibits both graded and bistable behaviors and accounts for the onset and resolution of mixed lineage patterns during cell fate determination.

Animals↗

PubMed2005

Control of genotypic allelic inclusion through TCR surface expression.

To gain insight into the molecular causes and functional consequences of allelic inclusion of TCR alpha-chains, we develop a computational model for thymocyte selection in which the signal that determines cell fate depends on surface expression. Analysis of receptor pairs on selected dual TCR cells reveals that allelic inclusion permits both autoreactive TCR and receptors not in the single TCR cell repertoire to be selected. However, in comparison with earlier theoretical studies, relatively few dual TCR cells display receptors with high avidity for thymic ligands because their alpha-chains compete aggressively for the beta-chain, which hinders rescue from clonal deletion. This feature of the model makes clear that allelic inclusion does not in itself compromise central tolerance. A specific experiment based on modulation of TCR surface expression levels is proposed to test the model.

Alleles↗