Ware, C. F. | bioRxiv Science

bioRxiv2020

Development of follicular dendritic cells in lymph nodes depends on retinoic acid mediated signaling

Specialized stromal cells occupy and help define B- and T cell domains, which is crucial for proper functioning of our immune system. Signaling through lymphotoxin and TNF-receptors is crucial for development of different stromal subsets which are thought to arise from a common precursor. However, mechanisms that control the selective generation of the different stromal phenotypes are not known. Here we show that in mice, retinoic acid mediated signaling is important for the differentiation of precursors towards the Cxcl13pos follicular dendritic cell (FDC) lineage, while blocking lymphotoxin mediated Ccl19pos fibroblastic reticular cell (FRC) lineage differentiation. Consequently, we see at day of birth Cxcl13posCcl19neg/low and Cxcl13neg/lowCcl19pos cells within neonatal lymph nodes. Furthermore, ablation of retinoic acid receptor signaling in stromal precursors early after birth reduces Cxcl13 expression, while in addition, complete blockade of retinoic acid signaling prevents formation of FDC networks in lymph nodes.

immunology↗

bioRxiv2020

Deletion of immune evasion genes provides an effective vaccine design for tumor-associated herpesviruses

Vaccines based on live attenuated viruses often induce broad, multifaceted immune responses. However, they also usually sacrifice immunogenicity for attenuation. It is particularly difficult to elicit an effective vaccine for herpesviruses due to an armament of immune evasion genes and a latent phase. Here, to overcome the limitation of attenuation, we developed a rational herpesvirus vaccine in which viral immune evasion genes were deleted to enhance immunogenicity while also attaining safety. To test this vaccine strategy, we utilized murine gammaherpesvirus-68 (MHV-68) as a proof-of-concept model for the cancer-associated human {gamma}-herpesviruses, Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus. We engineered a recombinant MHV-68 virus by targeted inactivation of viral antagonists of type I interferon (IFN-I) pathway and deletion of the latency locus responsible for persistent infection. This recombinant virus is highly attenuated with no measurable capacity for replication, latency, or persistence in immunocompetent hosts. It stimulates robust innate immunity, differentiates virus-specific memory T cells, and elicits neutralizing antibodies. A single vaccination affords durable protection that blocks the establishment of latency following challenge with the wild type MHV-68 for at least six months post-vaccination. These results provide a novel approach to effective vaccination against cancer-associated herpesviruses through the elimination of latency and key immune evasion mechanisms from the pathogen.

microbiology↗