Boosting BCG-primed mice with a recombinant adenovirus expressing M. tuberculosis antigen 85A by different routes has very different effects on protection against aerosol challenge with M. tuberculosis. Mice boosted intradermally make very strong splenic CD4 and CD8 Th1 cytokine responses to antigen 85A, but show no change in lung mycobacterial burden over BCG primed animals. In contrast intranasally boosted mice show greatly reduced mycobacterial burden and make a much weaker splenic response but a very strong lung CD4 and CD8 response to antigen 85A and an increased response to PPD. This is associated with the presence in the lung of multifunctional T cells, with high median fluorescence intensities and integrated median fluorescence intensities for IFNγ, IL-2 and TNF. In contrast, mice immunized with BCG alone have few antigen-specific cells in the lung and a low proportion of multi-functional cells although individual cells have high median fluorescence intensities. Successful immunization regimes appear to induce antigen-specific cells with abundant intracellular cytokine staining.
The KDM4/JMJD2 family of histone demethylases is amplified in human cancers. However, little is known about their physiologic or tumorigenic roles. We have identified a conserved and unappreciated role for the JMJD2A/KDM4A H3K9/36 tridemethylase in cell cycle progression. We demonstrate that JMJD2A protein levels are regulated in a cell cycle-dependent manner and that JMJD2A overexpression increased chromatin accessibility, S phase progression, and altered replication timing of specific genomic loci. These phenotypes depended on JMJD2A enzymatic activity. Strikingly, depletion of the only C. elegans homolog, JMJD-2, slowed DNA replication and increased ATR/p53-dependent apoptosis. Importantly, overexpression of HP1γ antagonized JMJD2A-dependent progression through S phase, and depletion of HPL-2 rescued the DNA replication-related phenotypes in jmjd-2(-/-) animals. Our findings describe a highly conserved model whereby JMJD2A regulates DNA replication by antagonizing HP1γ and controlling chromatin accessibility.
Identification of correlates of protection for infectious diseases including malaria is a major challenge and has become one of the main obstacles in developing effective vaccines. We investigated protection against liver-stage malaria conferred by vaccination with adenoviral and Modified Vaccinia Ankara (MVA) vectors expressing pre-erythrocytic malaria antigens. By classifying CD8+ T cells into effector (TE), effector/memory (TEM) and central memory (TCM) subsets using CD62L and CD127 markers, we found striking differences in T cell memory generation. While MVA induced accelerated TCM generation, which could be efficiently boosted by subsequent adenoviral administration, it failed to protect against malaria. In contrast, adenoviral (Ad) vectors, which permit persistent antigen delivery, elicit a prolonged TE and TEM response that requires long intervals for an efficient boost. A preferential TEM phenotype was maintained in liver, blood and spleen following Ad/MVA prime-boost regimens and animals were protected against malaria sporozoite challenge. Blood CD8+ TEM cells correlated with protection against malaria liver-stage infection, assessed by estimation of number of parasites emerging from the liver into the blood. The protective ability of antigen-specific TEM cells was confirmed by transfer experiments into naive recipient mice. Thus, we identify persistent CD8 TEM populations as essential for vaccine-induced pre-erythrocytic protection against malaria, a finding that has important implications for logical vaccine design.
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