Stochastic gene expression during lineage specification of single T helper lymphocytes

The adaptive immune system is an extraordinarily diverse inventory comprised of highly specialized cells, the differentiation of which requires numerous lineage specifications at various developmental stages. The precise control of immune cell differentiation and the delicate balance of their population composition are crucial for effective protection against infectious environmental agents, without triggering autoimmune responses or allergies. It is therefore important to understand at the molecular level in individual cells how lineage commitment is regulated. I explored the heterogeneous gene expression during the lineage specification of single T helper cells, by quantitatively measuring mRNA and protein levels. I have discovered a paradigm of cell lineage specification governed by the signaling interplay between extracellular cues and intracellular transcriptional factors, where the strength of extracellular signaling dominates over the intracellular signaling components. In the presence of extracellular cues, T helper cells stochastically acquire any intermediate Thl/Th2 states. The states of T helper cells can be gradually tuned by depriving availability of extracellular cytokines, which are produced stochastically by a small subpopulation of cells. When extracellular cues are removed, the weak intracellular signaling network reveals its effect, leading to classic mutual exclusion of antagonistic transcriptional factors.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biological Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2012

Author dc:creator

• Fang, Miaoqing

Advisor dc:contributor.advisor

• Alexander van Oudenaarden and Harvey Lodish.

• Biological Engineering.

Statement dc:rights

• MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/78138

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/78138