Allelic exclusion and differentiation by protein kinase C-mediated signals in immature thymocytes

Michie, A.M. , Soh, J.-W., Hawley, R.G., Weinstein, I.B. and Zuniga-Pflucker, J.C. (2001) Allelic exclusion and differentiation by protein kinase C-mediated signals in immature thymocytes. Proceedings of the National Academy of Sciences of the United States of America, 98(2), pp. 609-614. (doi: 10.1073/pnas.98.2.609)

Abstract

Pre-T cell receptor (preTCR)-derived signals mediate the transition of thymocytes from the CD4− CD8− double-negative (DN) to CD4+ CD8+ double-positive stage of T lymphocyte development. This progression, termed β-selection, is limited to thymocytes that have generated a functional TCR-β chain able to associate with pTα to form the preTCR complex. Formation of the preTCR complex not only induces differentiation, survival, and proliferation of DN thymocytes; it also inhibits further TCR-β gene rearrangement through an ill-defined process known as allelic exclusion. The signaling pathways controlling this critical developmental checkpoint have not been characterized. Here we demonstrate that formation of the preTCR complex leads to the activation of protein kinase C (PKC), and that activation of PKC is necessary for the differentiation and expansion of DN thymocytes. Importantly, we also show that allelic exclusion at the TCR-β gene loci is enforced by PKC-mediated signals. These results define PKC as a central mediator of both differentiation and allelic exclusion during thymocyte development.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Michie, Professor Alison
• Authors: Michie, A.M., Soh, J.-W., Hawley, R.G., Weinstein, I.B., and Zuniga-Pflucker, J.C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Proceedings of the National Academy of Sciences of the United States of America
• Publisher: National Academy of Sciences
• ISSN: 0027-8424
• ISSN (Online): 1091-6490