Discovering effector domains in human transcription factors.

Genomic studies are transforming knowledge about the epigenetic, transcription factor, and 3D landscapes of the genome. However, comprehensive information is lacking about the effector domains used by transcription factors to influence gene expression. Addressing this gap, DelRosso et al.

One degree of separation: urgent questions surrounding new USA laws in women's healthcare.

The criminalization of women's healthcare in many USA states has created uncertainty about women's access to evidence-based medical care and will affect the physical, mental, and emotional health and well-being of women. This article is intended to start a discussion on this complex topic in the immunology community.

Topologically associating domains are disrupted by evolutionary genome rearrangements forming species-specific enhancer connections in mice and humans.

Distinguishing between conserved and divergent regulatory mechanisms is essential for translating preclinical research from mice to humans, yet there is a lack of information about how evolutionary genome rearrangements affect the regulation of the immune response, a rapidly evolving system. The current model is topologically associating domains (TADs) are conserved between species, buffering evolutionary rearrangements and conserving long-range interactions within a TAD. However, we find that TADs frequently span evolutionary translocation and inversion breakpoints near genes with species-specific expression in immune cells, creating unique enhancer-promoter interactions exclusive to the mouse or human genomes.

Conservation and divergence in gene regulation between mouse and human immune cells deserves equal emphasis.

Model organisms such as mice are important for basic research and serve as valuable tools in preclinical translational studies. A challenge with translating findings from mice to humans is identifying and separating evolutionarily conserved mechanisms in the immune system from those diverging between species. A significant emphasis has been placed on defining conserved gene regulation principles, with divergent mechanisms often overlooked.

Are You There? Genetic Variation Impacts Long-Distance Connections in Diabetes.

A new study by Fasolino et al. defines how genetic variation in a mouse model of type 1 diabetes mellitus (T1DM) affects long-distance genomic interactions. The research has widespread implications for understanding how genetic diversity impacts disease susceptibility, and raises important concepts about mechanisms that can be influenced by genetic diversity between individuals.

Inhibition of IL-2 responsiveness by IL-6 is required for the generation of GC-T cells.

Sustained T cell receptor (TCR) stimulation is required for maintaining germinal center T follicular helper (GC-T) cells. Paradoxically, TCR activation induces interleukin-2 receptor (IL-2R) expression and IL-2 production, thereby initiating a feedback loop of IL-2 signaling that normally inhibits T cells. It is unclear how GC-T cells can receive prolonged TCR signaling without succumbing to the detrimental effects of IL-2.

Defining Genetic Variation in Widely Used Congenic and Backcrossed Mouse Models Reveals Varied Regulation of Genes Important for Immune Responses.

Genetic variation influences how the genome is interpreted in individuals and in mouse strains used to model immune responses. We developed approaches to utilize next-generation sequencing datasets to identify sequence variation in genes and enhancer elements in congenic and backcross mouse models. We defined genetic variation in the widely used B6-CD45.

T-bet Transcription Factor Promotes Antibody-Secreting Cell Differentiation by Limiting the Inflammatory Effects of IFN-γ on B Cells.

Although viral infections elicit robust interferon-γ (IFN-γ) and long-lived antibody-secreting cell (ASC) responses, the roles for IFN-γ and IFN-γ-induced transcription factors (TFs) in ASC development are unclear. We showed that B cell intrinsic expression of IFN-γR and the IFN-γ-induced TF T-bet were required for T-helper 1 cell-induced differentiation of B cells into ASCs. IFN-γR signaling induced Blimp1 expression in B cells but also initiated an inflammatory gene program that, if not restrained, prevented ASC formation.

Deficiency of Socs3 leads to brain-targeted EAE via enhanced neutrophil activation and ROS production.

Dysregulation of the JAK/STAT signaling pathway is associated with Multiple Sclerosis (MS) and its mouse model, Experimental Autoimmune Encephalomyelitis (EAE). Suppressors Of Cytokine Signaling (SOCS) negatively regulate the JAK/STAT pathway. We previously reported a severe, brain-targeted, atypical form of EAE in mice lacking Socs3 in myeloid cells (Socs3ΔLysM), which is associated with cerebellar neutrophil infiltration.

Defining Barriers that Impede Choices.

Committing to a differentiation pathway means leaving alternative pathways behind. Adoue et al. (2019) report that the H3K9-methyltrasferase Setdb1 plays a role in inhibiting the Th1 program in committed Th2 cells, and mechanistically, its role might relate to the selective targeting of endogenous retroviruses adjacent to Th1 enhancers.

Metabolites, genome organization, and cellular differentiation gene programs.

The nutrient environment and metabolism play a dynamic role in cellular differentiation and research is elucidating the mechanisms that contribute to this process. Metabolites serve as an effective bridge that helps to translate information about nutrient states into specific interpretations of the genome. Part of this activity relates to the role for metabolites in regulating epigenetic processes as well as a newly appreciated role for metabolites in the regulation of genome organization.

Connections Between Metabolism and Epigenetics in Programming Cellular Differentiation.

Researchers are intensifying efforts to understand the mechanisms by which changes in metabolic states influence differentiation programs. An emerging objective is to define how fluctuations in metabolites influence the epigenetic states that contribute to differentiation programs. This is because metabolites such as S-adenosylmethionine, acetyl-CoA, α-ketoglutarate, 2-hydroxyglutarate, and butyrate are donors, substrates, cofactors, and antagonists for the activities of epigenetic-modifying complexes and for epigenetic modifications.

Inhibition of STAT3 Signaling Reduces IgA1 Autoantigen Production in IgA Nephropathy.

Introduction: IgA nephropathy is a chronic renal disease characterized by mesangial immunodeposits that contain autoantigen, which is aberrantly glycosylated IgA1 with some hinge-region -glycans deficient in galactose. Macroscopic hematuria during an upper respiratory tract infection is common among patients with IgA nephropathy, which suggests a connection between inflammation and disease activity. Interleukin-6 (IL-6) is an inflammatory cytokine involved in IgA immune response.

Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection.

Interleukin 2 (IL-2) promotes Foxp3 regulatory T (T) cell responses, but inhibits T follicular helper (T) cell development. However, it is not clear how IL-2 affects T follicular regulatory (T) cells, a cell type with properties of both T and T cells. Using an influenza infection model, we found that high IL-2 concentrations at the peak of the infection prevented T cell development by a Blimp-1-dependent mechanism.

CCCTC-Binding Factor Translates Interleukin 2- and α-Ketoglutarate-Sensitive Metabolic Changes in T Cells into Context-Dependent Gene Programs.

Despite considerable research connecting cellular metabolism with differentiation decisions, the underlying mechanisms that translate metabolite-sensitive activities into unique gene programs are still unclear. We found that aspects of the interleukin-2 (IL-2)-sensitive effector gene program in CD4 and CD8 T cells in type 1 conditions (Th1) were regulated by glutamine and alpha-ketoglutarate (αKG)-induced events, in part through changes in DNA and histone methylation states. We further identified a mechanism by which IL-2- and αKG-sensitive metabolic changes regulated the association of CCCTC-binding factor (CTCF) with select genomic sites.

Protein Kinase CK2 Controls the Fate between Th17 Cell and Regulatory T Cell Differentiation.

CK2 is a highly conserved and pleiotropic serine/threonine kinase that promotes many prosurvival and proinflammatory signaling pathways, including PI3K/Akt/mTOR and JAK/STAT. These pathways are essential for CD4 T cell activation and polarization, but little is known about how CK2 functions in T cells. In this article, we demonstrate that CK2 expression and kinase activity are induced upon CD4 T cell activation.

Transcriptional regulation of T cell metabolism.

T cells express specific metabolic programs to promote diverse cellular differentiation states. The activation of naïve T cells upregulates the expression of genes encoding components of the glycolysis, glutaminolysis, and lipid biosynthesis pathways to promote robust proliferation and effector T cell activity. In contrast, memory T cells downregulate these pathways and predominantly rely on catabolic pathways for long-term survival.

TCR-Signaling Events in Cellular Metabolism and Specialization.

Engaging the T cell receptor (TCR) with peptide:MHC complexes initiates a cascade of signaling events that activates T cells in an antigen-specific manner. It is now clear that multiple inputs, including the strength of TCR signaling, co-stimulation, and the cytokine environment, impact T cell specialization decisions in the context of specific pathogenic encounters. Additionally, it is now appreciated that these same stimuli direct cellular metabolism programs.

Bcl-6 directly represses the gene program of the glycolysis pathway.

Despite the increasing knowledge of the molecular events that induce the glycolysis pathway in effector T cells, very little is known about the transcriptional mechanisms that dampen the glycolysis program in quiescent cell populations such as memory T cells. Here we found that the transcription factor Bcl-6 directly repressed genes encoding molecules involved in the glycolysis pathway, including Slc2a1, Slc2a3, Pkm and Hk2, in type 1 helper T cells (TH1 cells) exposed to low concentrations of interleukin 2 (IL-2). Thus, Bcl-6 had a role opposing the IL-2-sensitive glycolytic transcriptional program that the transcription factors c-Myc and HIF-1α promote in effector T cells.

Roles for helper T cell lineage-specifying transcription factors in cellular specialization.

The development of specialized helper T cells has garnered much attention because of their critical role in coordinating the immune response to invading pathogens. Recent research emphasizing novel functions for specialized helper T cells in a variety of infectious disease settings, as well as autoimmune states, has reshaped our view on the capabilities of helper T cells. Notably, one previously underappreciated aspect of the lifespan of helper T cells is that they often retain the capacity to respond to changes in the environment by altering the composition of helper T cell lineage-specifying transcription factors they express, which, in turn, changes their phenotype.