f Herpesvirus entry mediator (HVEM) is one of several cell surface proteins herpes simplex virus (HSV) uses for attachment/entry. HVEM regulates cellular immune responses and can also increase cell survival. Interestingly, latency-associated transcript (LAT), the only viral gene consistently expressed during neuronal latency, enhances latency and reactivation by promoting cell survival and by helping the virus evade the host immune response. However, the mechanisms of these LAT activities are not well understood. We show here for the first time that one mechanism by which LAT enhances latency and reactivation appears to be by upregulating HVEM expression. HSV-1 latency/reactivation was significantly reduced in Hvem ؊/؊ mice, indicating that HVEM plays a significant role in HSV-1 latency/reactivation. Furthermore, LAT upregulated HVEM expression during latency in vivo and also when expressed in vitro in the absence of other viral factors. This study suggests a mechanism whereby LAT upregulates HVEM expression potentially through binding of two LAT small noncoding RNAs to the HVEM promoter and that the increased HVEM then leads to downregulation of immune responses in the latent microenvironment and increased survival of latently infected cells. Thus, one of the mechanisms by which LAT enhances latency/reactivation appears to be through increasing expression of HVEM.

SUMMARY γδ T cells rapidly secrete inflammatory cytokines at barrier sites that aid in protection from pathogens, however mechanisms limiting inflammatory damage remain unclear. We found that retinoid-related orphan receptor gamma-t (RORγt) and interleukin (IL)-7 influence γδ T cell homeostasis and function by regulating expression of the inhibitory receptor, B and T Lymphocyte Attenuator (BTLA). The transcription factor RORγt, via its activating function-2 domain, repressed Btla transcription, whereas IL-7 increased BTLA levels on the cell surface. BTLA expression limited γδ T cell numbers and sustained normal γδ T cell subset frequencies by restricting IL-7 responsiveness and expansion of the CD27−RORγt+ population. BTLA also negatively regulated IL-17 and TNF production in CD27− γδ T cells. Consequently, BTLA-deficient mice exhibit enhanced disease in a γδ T cell-dependent model of dermatitis, while BTLA agonism reduced inflammation. Therefore, by coordinating expression of BTLA, RORγt and IL-7 balance suppressive and activation stimuli to regulate γδ T cell homeostasis and inflammatory responses.

Innate lymphoid cells (ILCs) encompass a diverse array of lymphocyte subsets with unique phenotype that initiate inflammation and provide host defenses in specific microenvironments. In this report we identify a rare human CD4+CD3− innate-like lymphoid population with high TNF expression that is enriched in blood from patients with rheumatoid arthritis. These CD4+CD3− cells belong to the T cell lineage but the lack of antigen receptor at the cell surface renders them nonresponsive to TCR-directed stimuli. By developing a culture system that sustains survival, we show that CD4+CD3− innate-like T cells display IL-7-dependent induction of surface lymphotoxin-αβ (LTαβ) demonstrating their potential to modify tissue microenvironments. Furthermore, expression of CCR6 on CD4+CD3− population defines a CD127high subset that is highly responsive to IL-7. This CD4+CD3− population is enriched in the peripheral blood from rheumatoid arthritis patients suggesting a link to their involvement in chronic inflammatory disease.

Genome-wide co-expression analysis is often used for annotating novel gene functions from high-dimensional data. Here, we developed an R package with a Shiny visualization app that creates immuno-networks from RNAseq data using a combination of Weighted Gene Co-expression Network Analysis (WGCNA), xCell immune cell signatures, and Bayesian Network Learning. Using a large publicly available RNAseq dataset we generated a Gene Module-Immune Cell (GMIC) network that predicted causal relationships between DEAH-box RNA helicase (DHX)15 and genes associated with humoral immunity, suggesting that DHX15 may regulate B cell fate. Deletion of DHX15 in mouse B cells led to impaired lymphocyte development, reduced peripheral B cell numbers, and dysregulated expression of genes linked to antibody-mediated immune responses similar to the genes predicted by the GMIC network. Moreover, antigen immunization of mice demonstrated that optimal primary IgG1 responses required DHX15. Intrinsic expression of DHX15 was necessary for proliferation and survival of activated of B cells. Altogether, these results support the use of co-expression networks to elucidate fundamental biological processes.