Pathophysiological mechanisms by which the risk to develop MS may increase after selleck kinase inhibitor childhood are largely unknown. Much of our current knowledge regarding the assumed auto-immune pathogenesis

of MS derives from EAE, the animal model of MS. Activated, myelin-reactive CD4+ Th1 cells are thought to have a central role in the pathogenesis of both MS and EAE [4]. Initial activation of CD4+ T cells occurs through recognition of Ag presented in the context of MHC class II (MHC II). Processing of Ag and presentation of linearized peptides is provided by MHC II-expressing APCs [5], such as myeloid monocytes and macrophages, DCs as well as B cells. Following Ag recognition, efficient activation of CD4+ T cells requires further ligation with co-stimulatory molecules expressed on the APC surface. Besides the density of MHC II expression [6, 7] and the composition of co-stimulatory molecules CAL101 [8, 9], the fate of the corresponding T cell to either

differentiate into a proinflammatory Th1 or Th17 phenotype or to alternatively develop into an anti-inflammatory Th2 cell or Treg cell is determined by the cytokine milieu present at the site of APC-T-cell interaction [10, 11]. Thus, a variety of signals provided by the APCs is required for efficient development of proinflammatory T cells in vivo. Based on this conception, we tested in the EAE model whether an age-associated alteration of innate immune cell function may determine Ixazomib chemical structure susceptibility to CNS autoimmune

disease. EAE is traditionally induced by active immunization with CNS autoAg in 8- to 20-week-old mice, as EAE susceptibility is maximal at this age [12]. To establish that susceptibility may be lower at an earlier age, EAE was induced in C57BL/6 mice at the age of 2 weeks using an active immunization protocol with MOG p35–55 in CFA and PTx. As indicated in Figure 1A, none of the 2-week-old mice showed any clinical signs of EAE (0/13), whereas 8/8 mice at the age of 8 weeks developed ascending paralysis around day 10 after immunization. Twelve days after immunization, a subgroup of mice was analyzed for development of myelin-reactive T cells. As shown in Figure 1B, splenocytes from 2-week-old mice revealed a strongly reduced proliferation of T cells in response to MOG p35–55. Furthermore, secretion of IFN-γ and IL-17 was decreased suggesting that EAE resistance of 2-week-old mice relates to an inability of younger mice to generate encephalitogenic T cells. In order to elucidate mechanistically why young mice are unable to generate EAE-inducing, proinflammatory T cells, we first confirmed that the frequency of peripheral T cells was unchanged. As indicated in Figure 2A, there was no difference in 2- or 8-week-old mice in the frequency of total CD3+ T cells as well as the ratio of CD4+ to CD8+ T cells.