1410 Veronica Basso et al. DOI 10.1002/eji.201040892 Eur. J. Immunol. 2011. 41: 1410–1419 Absence of Rac1 and Rac3 GTPases in the nervous system hinders thymic, splenic and immune- competence development Veronica Basso1, Sara Corbetta2, Sara Gualdoni2, Diletta Tonoli2, Pietro Luigi Poliani3, Francesca Sanvito4, Claudio Doglioni4,5, Anna Mondino 1 and Ivan de Curtis 2,5 1 Lymphocyte Activation Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientiﬁc Institute, Milan, Italy 2 Cell Adhesion Unit, Division of Neuroscience, San Raffaele Scientiﬁc Institute, Milan, Italy 3 Department of Pathology, University of Brescia Medical School, Brescia, Italy 4 Pathology Unit, San Raffaele Scientiﬁc Institute, Milan, Italy 5 Vita-Salute San Raffaele University, Milan, Italy The nervous system inﬂuences organ development by direct innervation and the action of hormones. We recently showed that the speciﬁc absence of Rac1 in neurons (Rac1N) in a Rac3-deﬁcient (Rac3KO) background causes motor behavioural defects, epilepsy, and premature mouse death around postnatal day 13. We report here that Rac1N/Rac3KO mice display a progressive loss of immune-competence. Comparative longitudinal analysis of lymphoid organs from control, single Rac1N or Rac3KO, and double Rac1N/Rac3KO mutant animals showed that thymus development is preserved up to postnatal day 9 in all animals, but is impaired in Rac1N/Rac3KO mice at later times. This is evidenced by a drastic reduction in thymic cell numbers. Cell numbers were also reduced in the spleen, leading to splenic tissue disarray. Organ involution occurs in spite of unaltered thymocyte and lymphocyte subset composition, and proper mature T-cell responses to polyclonal stimuli in vitro. Suboptimal thymus innervation by tau-positive neuronal terminals possibly explains the suboptimal thymic output and arrested thymic development, which is accompanied by higher apoptotic rates. Our results support a role for neuronal Rac1 and Rac3 in dictating proper lymphoid organ development, and suggest the existence of lymphoid-extrinsic mechanisms linking neural defects to the loss of immune-competence. Keywords: Immune-competence . Neuroimmunology . Neurons . Rac GTPases . Thymus Supporting Information available online Introduction Over the past several years complex bidirectional interactions between the nervous system and the immune system have been Correspondence: Dr. Anna Mondino e-mail: anna.mondino@hsr.it & 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim identiﬁed, which seem necessary to maintain homeostasis in both systems and to regulate the immune response. Sympathetic innervation of lymphoid organs is involved in the control of the immune responses [1]. In particular, the central nervous system may inﬂuence immune cell function by the sympathetic nerve Co-senior authors. www.eji-journal.eu