Tolerance and Immunity: Opposite Outcomes of Microbial Antigen Stimulation

Abstract: The immune system is remarkable in many ways. It exerts immunity to defend us from foreign pathogens, while it is also responsible for maintaining tolerance to avoid autoimmune diseases and allergy. This thesis includes three separate papers concerning both tolerance and immunity. In paper I we report that repeated antigen stimulation results in an increased proportion of Foxp3+ cells in the CD4+ population of T cells in mice. This was caused by a decreased number of antigen-reactive conventional CD4+ T cells rather than by de novo development of Foxp3+ Tregs. Proliferation of naive transferred CD4+ T cells was inhibited in repeatedly immunized mice and cells transferred from such mice into naive recipients were shown to be anergic. Finally, we demonstrate that the in vitro anergy is partially dependent on Foxp3+ cells whereas the in vivo anergy is not. In paper II, bone marrow-derived dendritic cells from IFN-β-/- mice were used to study the role of IFN-β in TLR2-mediated induction of iNOS. We demonstrate that the TLR2 ligands LTA and Pam3Cys induce the expression of iNOS in an IFN-β dependent manner. Furthermore, iNOS activity induced by these ligands did not require receptor internalization or endosomal maturation, and was differentially dependent on the TRIF- and IRF3 molecules. In paper III we have investigated the impact of in vivo 5757-treatment on cells in lymph nodes and spleen of steady state mice. We show that the cell number of a specific DC-subset, CD4+CD8α-, is selectively reduced in the spleen of 5757-treated mice. The reduction was reversible and was not caused by decreased cell division or increased apoptosis. Finally, the overall structure of the marginal zone, where CD4+CD8α- DCs normally reside, remained intact in mice treated with 5757, ruling out the hypothesis that these DCs would emigrate from the spleen because of a disrupted marginal zone.