IMMUNOBIOLOGY Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in

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 target-ing to achieve hematopoietic stem cell (HSC) – or T-cell lineage–specific deletion of Rac1 or Rac1/Rac2 by crossbreeding 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 T-cell development in thymus and peripheral organs, whereas deletion of Rac1 moder-ately 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 reduced immature CD4CD8 and mature CD4 populations in thymus as well as 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. (4) Rac1/Rac2 deletion suppressed T-cell receptor–mediated pro-liferation, IL-2 production, and Akt activa-tion 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 regu-lating survival and proliferation signals. (Blood. 2008;112:1767-1775