Slamf receptors: Modulators of Phagocyte Immune Responses

Boaz Job Van Driel

Research output: PhD ThesisPhD thesis

Abstract

Signaling Lymphocyte Activation Molecule family (Slamf) receptors can operate in three distinct modes. Slamf receptors can dictate the extent of immune responses, thereby maneuvering immunity to the optimal zone between immunopathology or autoimmunity and weak, ineffective immune responses. A second mode of action affects the development of leukocytes. Lastly, Slamf receptors can have direct functional involvement in immune effector mechanisms. This thesis describes such direct functions of Slamf receptors in phagocytes. The generation of reactive oxygen species (ROS) and nitric oxide (NO) represent a set of anti-microbial mechanisms in phagocytes. Slamf1 clustering, caused by interactions with bacterial entities or by other means, results in the formation of the NADPH-oxidase 2 enzyme-complex, which produces ROS. This classic paradigm that production of ROS by phagocytes is instrumental in their bactericidal activity is complemented by more recent studies that have established a role in cell adhesion and migration. Slamf1 acts in phagocytic cells as an enhancer of cell motility. Subsequent experiments showed that the effect on phagocyte motility of Slamf8, which is the receptors that appears to – in effect – antagonize Slamf1’s enhancement of reactive oxygen species production, is also reversibly upheld. These phenotypic parallels appear to be linked, as inhibitions of ROS production resulted in a loss of the migration phenotypes. In vivo, Slamf1 contributes to the development of colitis in mice. It regulates the appearance of pro-inflammatory monocytes in inflamed intestinal tissues. The killing of bacteria is an important feature of mucosal immunity, especially in the context of inflammation. Slamf1 expedites the killing of specific Gram− bacteria by phagocytes. However, the effect of Slamf1 on this process appears to be subordinate to the cell migration phenotype. Slamf6, which is the closest functional relative of Slamf1, also engages Gram− bacteria, including Citrobacter rodentium. In addition to adaptive immune cells – Rag−⁄− animals succumb to Citrobacter rodentium infections – colonic phagocytes contribute to immunity to this bacterium. Slamf6−⁄−Rag−⁄− mice survive this colitis, develop a very mild immune response, and uphold a better mucosal barrier function in the face of this bacterium. These mice produce more IL-22, which is a key cytokine for the maintenance of the mucosal integrity. The production of IL-22 depends on the detection of Citrobacter rodentium by lumen-probing phagocytes. We have therefore hypothesized that Slamf6 is involved in the pathway by engaging the bacterium. Of importance, antibodies that block Slamf1 or Slamf6 reduce colitis in mice. We observe consistent parallels between the phenotypes of mice deficient for Slamf1, Slamf8, or Slamf6 and mice that received the respective monoclonal antibodies during the experiments. This suggests that engagement with a ligand is required for the in vivo functions of these receptors, regardless whether the ligands are homophilic or of bacterial origin. Thus, Slamf1 and Slamf6 operate in phagocytic cells. When they do, these receptors tip the scales toward inflammation. Slamf1 enhances phagosome progression, but also utilizes aspects of this mechanism to influence cell motility. As such, Slamf1 contributes to de development of colitis. Slamf6 can engage bacteria and – during bacterial colitis – drives pro-inflammatory processes
Original languageEnglish
QualificationDoctor (dr.)
Awarding Institution
Supervisors/Advisors
  • Clevers, Hans, Promotor
  • Terhorst, C., Promotor, External person
Award date19 Oct 2015
Publisher
Print ISBNs978-90-9029311-0
Publication statusPublished - 2015

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