A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production

The Psmb11-encoded β5t subunit of the thymoproteasome, which is specifically expressed in cortical thymic epithelial cells (cTECs), is essential for the optimal positive selection of functionally competent CD8+ T cells in mice. Here, we report that a human genomic PSMB11 variation, which is detectable at an appreciable allele frequency in human populations, alters the β5t amino acid sequence that affects the processing of catalytically active β5t proteins. The introduction of this variation in the mouse genome revealed that the heterozygotes showed reduced β5t expression in cTECs and the homozygotes further exhibited reduction in the cellularity of CD8+ T cells. No severe health problems were noticed in many heterozygous and 5 homozygous human individuals. Long-term analysis of health status, particularly in the homozygotes, is expected to improve our understanding of the role of the thymoproteasome-dependent positive selection of CD8+ T cells in humans

Role of interleukin-25 in development of spontaneous arthritis in interleukin-1 receptor antagonist-deficient mice

Interleukin (IL)-25, which is a member of the IL-17 family of cytokines, induces production of such Th2 cytokines as IL-4, IL-5, IL-9 and/or IL-13 by various types of cells, including Th2 cells, Th9 cells and group 2 innate lymphoid cells (ILC2). On the other hand, IL-25 can suppress Th1- and Th17-associated immune responses by enhancing Th2-type immune responses. Supporting this, IL-25 is known to suppress development of experimental autoimmune encephalitis, which is an IL-17-mediated autoimmune disease in mice. However, the role of IL-25 in development of IL-17-mediated arthritis is not fully understood. Therefore, we investigated this using IL-1 receptor antagonist-deficient (IL-1Ra-/-) mice, which spontaneously develop IL-17-dependent arthritis. However, development of spontaneous arthritis (incidence rate, disease severity, proliferation of synovial cells, infiltration of PMNs, and bone erosion in joints) and differentiation of Th17 cells in draining lymph nodes in IL-25-/- IL-1Ra-/- mice were similar to in control IL-25+/+ IL-1Ra-/- mice. These observations indicate that IL-25 does not exert any inhibitory and/or pathogenic effect on development of IL-17-mediated spontaneous arthritis in IL-1Ra-/- mice