IL-17 is a cytokine that induces neutrophil-mediated inflammation, but its role in protective immunity against intracellular bacterial infection remains unclear. In the present study, we demonstrate that IL-17 is an important cytokine not only in the early neutrophil-mediated inflammatory response, but also in T cell-mediated IFN-γ production and granuloma formation in response to pulmonary infection by Mycobacterium bovis bacille Calmette-Guérin (BCG). IL-17 expression in the BCG-infected lung was detected from the first day after infection and the expression depended on IL-23. Our observations indicated that γδ T cells are a primary source of IL-17. Lung-infiltrating T cells of IL-17-deficient mice produced less IFN-γ in comparison to those from wild-type mice 4 wk after BCG infection. Impaired granuloma formation was also observed in the infected lungs of IL-17-deficient mice, which is consistent with the decreased delayed-type hypersensitivity response of the infected mice against mycobacterial Ag. These data suggest that IL-17 is an important cytokine in the induction of optimal Th1 response and protective immunity against mycobacterial infection.

The gene Bcl11b, which encodes zinc finger proteins, and its paralog, Bcl11a, are associated with immune-system malignancies. We have generated Bcl11b-deficient mice that show a block at the CD4-CD8- double-negative stage of thymocyte development without any impairment in cells of B- or gammadelta T cell lineages. The Bcl11b-/- thymocytes showed unsuccessful recombination of V(beta) to D(beta) and lacked the pre-T cell receptor (TCR) complex on the cell surface, owing to the absence of Tcrb mRNA expression. In addition, we saw profound apoptosis in the thymus of neonatal Bcl11b-/- mice. These results suggest that Bcl11b is a key regulator of both differentiation and survival during thymocyte development.

IL-17A is originally identified as a proinflammatory cytokine that induces neutrophils. Although IL-17A production by CD4+ Th17 T cells is well documented, it is not clear whether IL-17A is produced and participates in the innate immune response against infections. In the present report, we demonstrate that IL-17A is expressed in the liver of mice infected with Listeria monocytogenes from an early stage of infection. IL-17A is important in protective immunity at an early stage of listerial infection in the liver because IL-17A-deficient mice showed aggravation of the protective response. The major IL-17A-producing cells at the early stage were TCR γδ T cells expressing TCR Vγ4 or Vγ6. Interestingly, TCR γδ T cells expressing both IFN-γ and IL-17A were hardly detected, indicating that the IL-17A-producing TCR γδ T cells are distinct from IFN-γ-producing γδ T cells, similar to the distinction between Th17 and Th1 in CD4+ T cells. All the results suggest that IL-17A is a newly discovered effector molecule produced by TCR γδ T cells, which is important in innate immunity in the liver.

Summary Presenilins play essential roles in memory formation, synaptic function, and neuronal survival. Mutations in the Presenilin-1 (PSEN1) gene are the major cause of familial Alzheimer’s disease (FAD). How PSEN1 mutations cause FAD is unclear, and pathogenic mechanisms based on gain or loss of function have been proposed. Here, we generated Psen1 knockin (KI) mice carrying the FAD mutation L435F or C410Y. Remarkably, KI mice homozygous for either mutation recapitulate the phenotypes of Psen1−/− mice. Neither mutation altered Psen1 mRNA expression, but both abolished γ-secretase activity. Heterozygosity for the KI mutation decreased production of Aβ40 and Aβ42, increased the Aβ42/Aβ40 ratio, and exacerbated Aβ deposition. Furthermore, the L435F mutation impairs hippocampal synaptic plasticity and memory and causes age-dependent neurodegeneration in the aging cerebral cortex. Collectively, our findings reveal that FAD mutations can cause complete loss of Presenilin-1 function in vivo, suggesting that clinical PSEN mutations produce FAD through a loss-of-function mechanism.