Abstract
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.
Highlights
Over the past several years complex bidirectional interactions between the nervous system and the immune system have been identified, which seem necessary to maintain homeostasis in both systems and to regulate the immune response
We found that the simultaneous inactivation of neuronal Rac1 and Rac3 causes specific defects in the development of the spleen and thymus of the Rac1 in neurons (Rac1N)/Rac3KO double KO mice, and a concomitant defect in the innervation of the thymus of Rac1N/Rac3KO mice
We found that at P13, the density of sympathetic innervation of the thymus was comparable in Rac1N/Rac3KO double mutants and control Rac3KO mutants, indicating that a defect at this level might not account for the observed phenotype (Fig. 8A and Supporting Information Fig. 7)
Summary
Over the past several years complex bidirectional interactions between the nervous system and the immune system have been 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]. The central nervous system may influence immune cell function by the sympathetic nerve. Immunomodulation 1411 fibres within lymphoid organs, which release norepinephrine that can bind to adrenergic receptors expressed by various cell types in the lymphoid organs [2]. The close proximity of sympathetic nerve terminals to immune cells provides a mechanism for the specific targeting of catecholamines to immune cells [3, 4]. Little is known about the role of, and the molecular mechanisms underlying, the innervation of the immune system
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