Submitted January 3, 2008
Accepted June 9, 2008
Rac GTPase isoforms, Rac1 and Rac2, play a redundant and crucial role in T-cell development
Fukun Guo, Jose A Cancelas, David Hildeman, David A Williams, and Yi Zheng*
Divisions of Experimental Hematology and Cancer Biology, and Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
Hoxworth Blood Center, University of Cincinnati, Cincinnati, Ohio, United States
Division of Hematology and Oncology, Boston Children's Hospital, Boston, MA, United States
* Corresponding author; email: yi.zheng{at}cchmc.org.
Rac GTPases have been implicated in the regulation of diverse functions in various blood cell lineages, but their role in T-cell development is not well understood. We have carried out conditional gene targeting to achieve hematopoietic stem cell- (HSC) or T-cell lineage-specific deletion of Rac1 or Rac1/Rac2 by cross-breeding the Mx-Cre or Lck-Cre transgenic mice with Rac1loxp/loxp or Rac1loxp/loxp
;Rac2-/- mice. We found that (1) HSC deletion of both Rac1 and Rac2 inhibited production of common lymphoid progenitors (CLPs) in bone marrow and suppressed subsequent T-cell development in thymus and peripheral organs, while deletion of Rac1 moderately affected CLP production and T-cell development; (2) T-cell specific deletion of Rac1 did not affect T-cell development, whereas deletion of both Rac1 and Rac2 significantly reduced immature CD4+CD8+ and mature CD4+ populations in thymus as well as mature CD4+ and CD8+ populations in spleen; (3) the developmental defects of Rac1/Rac2 knockout T-cells were associated with proliferation, survival, adhesion, and migration defects; and (4) Rac1/Rac2 deletion suppressed T-cell receptor mediated proliferation, IL2 production, and Akt activation in thymocytes. Thus, Rac1 and Rac2 have unique roles in CLP production and share a redundant but essential role in later stages of T-cell development by regulating survival and proliferation signals.
