Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset.

Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. Studies of human T1D immunobiology have predominantly focused on circulating immune cells in the blood, while mouse models suggest diabetogenic lymphocytes primarily reside in pancreas-draining lymph nodes (pLN). A comprehensive study of immune cells in human T1D was conducted using pancreas draining lymphatic tissues, including pLN and mesenteric lymph nodes, and the spleen from non-diabetic control, β cell autoantibody positive non-diabetic (AAb+), and T1D organ donors using complementary approaches of high parameter flow cytometry and CITEseq.

ABCs begin with ZEB2.

Age-associated B cells (ABCs) are a stable subset of memory B lymphocytes that develop during microbial infections and in autoimmune diseases. Despite growing appreciation of their phenotypic and functional characteristics, the transcriptional networks involved in ABC fate commitment and maintenance have remained elusive. In their recent publication, Dai et al.

Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies.

Pre-existing anti-human leukocyte antigen (HLA) allo-antibodies constitute a major barrier to transplantation. Current desensitization approaches fail due to ineffective depletion of allo-specific memory B cells (Bmems) and long-lived plasma cells (LLPCs). We evaluate the efficacy of chimeric antigen receptor (CAR) T cells targeting CD19 and B cell maturation antigen (BCMA) to eliminate allo-antibodies in a skin pre-sensitized murine model of islet allo-transplantation.

Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines.

Lipid nanoparticle (LNP)-formulated messenger RNA (mRNA) vaccineare a promising platform to prevent infectious diseases as demonstrated by the recent success of SARS-CoV-2 mRNA vaccines. To avoid immune recognition and uncontrolled inflammation, nucleoside-modified mRNA is used. However, such modification largely abrogates the innate immune responses that are critical to orchestrating robust adaptive immunity.

Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses.

Adjuvants are critical for improving the quality and magnitude of adaptive immune responses to vaccination. Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines have shown great efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the mechanism of action of this vaccine platform is not well-characterized. Using influenza virus and SARS-CoV-2 mRNA and protein subunit vaccines, we demonstrated that our LNP formulation has intrinsic adjuvant activity that promotes induction of strong T follicular helper cell, germinal center B cell, long-lived plasma cell, and memory B cell responses that are associated with durable and protective antibodies in mice.

Trivalent nucleoside-modified mRNA vaccine yields durable memory B cell protection against genital herpes in preclinical models.

Nucleoside-modified mRNA vaccines have gained global attention because of COVID-19. We evaluated a similar vaccine approach for preventing a chronic, latent genital infection rather than an acute respiratory infection. We used animal models to compare an HSV-2 trivalent nucleoside-modified mRNA vaccine with the same antigens prepared as proteins, with an emphasis on antigen-specific memory B cell responses and immune correlates of protection.

An AAV-based, room-temperature-stable, single-dose COVID-19 vaccine provides durable immunogenicity and protection in non-human primates.

The SARS-CoV-2 pandemic has affected more than 185 million people worldwide resulting in over 4 million deaths. To contain the pandemic, there is a continued need for safe vaccines that provide durable protection at low and scalable doses and can be deployed easily. Here, AAVCOVID-1, an adeno-associated viral (AAV), spike-gene-based vaccine candidate demonstrates potent immunogenicity in mouse and non-human primates following a single injection and confers complete protection from SARS-CoV-2 challenge in macaques.

The dynamic epigenetic regulation of the inactive X chromosome in healthy human B cells is dysregulated in lupus patients.

Systemic lupus erythematous (SLE) is a female-predominant disease characterized by autoimmune B cells and pathogenic autoantibody production. Individuals with two or more X chromosomes are at increased risk for SLE, suggesting that X-linked genes contribute to the observed sex bias of this disease. To normalize X-linked gene expression between sexes, one X in female cells is randomly selected for transcriptional silencing through X-chromosome inactivation (XCI), resulting in allele-specific enrichment of epigenetic modifications, including histone methylation and the long noncoding RNA XIST/Xist on the inactive X (Xi).

Immunogenicity of an AAV-based, room-temperature stable, single dose COVID-19 vaccine in mice and non-human primates.

The SARS-CoV-2 pandemic has affected more than 70 million people worldwide and resulted in over 1.5 million deaths. A broad deployment of effective immunization campaigns to achieve population immunity at global scale will depend on the biological and logistical attributes of the vaccine.

The Transcription Factor T-bet Resolves Memory B Cell Subsets with Distinct Tissue Distributions and Antibody Specificities in Mice and Humans.

B cell subsets expressing the transcription factor T-bet are associated with humoral immune responses and autoimmunity. Here, we examined the anatomic distribution, clonal relationships, and functional properties of T-bet and T-bet memory B cells (MBCs) in the context of the influenza-specific immune response. In mice, both T-bet and T-bet hemagglutinin (HA)-specific B cells arose in germinal centers, acquired memory B cell markers, and persisted indefinitely.

Impact of Interleukin-27p28 on T and B Cell Responses during Toxoplasmosis.

Interleukin-27 (IL-27) is a heterodimeric cytokine composed of the subunits IL-27p28 and EBi3, and while the IL-27 heterodimer influences T cell activities, there is evidence that IL-27p28 can have EBi3-independent activities; however, their relevance to infection is unclear. Therefore, the studies presented here compared how IL-27p28 transgenics and IL-27p28 mice responded to the intracellular parasite While the loss of IL-27p28 and its overexpression both result in increased susceptibility to , the basis for this phenotype reveals distinct roles for IL-27p28. As a component of IL-27, IL-27p28 is critical to limit infection-induced T cell-mediated pathology, whereas the ectopic expression of IL-27p28 reduced the effector T cell population and had a major inhibitory effect on parasite-specific antibody titers and a failure to control parasite replication in the central nervous system.

T-bet memory B cells: Generation, function, and fate.

B cells expressing the transcription factor T-bet have emerged as participants in a number of protective and pathogenic immune responses. T-bet B cells characteristically differentiate in response to combined Toll-like receptor and cytokine signaling, contribute to protective immunity against intracellular pathogens via IgG2 production and antibody-independent mechanisms, and are prone to produce autoantibodies. Despite recent advances, a number of questions remain regarding the basic biology of T-bet B cells and their functional niche within the immune system.

T-bet-expressing B cells during HIV and HCV infections.

T-bet-expressing B cells, first identified as perpetuators of autoimmunity, were recently shown to be critical for murine antiviral responses. While their role in human viral infections remains unclear, B cells expressing T-bet or demonstrating a related phenotype have been described in individuals chronically infected with HIV or HCV, suggesting these cells represent a component of human antiviral responses. In this review, we discuss the induction of T-bet in B cells following both HIV and HCV infections, the factors driving T-bet B cell expansions, T-bet's relationship to atypical memory B cells, and the consequences of T-bet induction.

T-bet+ B cells are induced by human viral infections and dominate the HIV gp140 response.

Humoral immunity is critical for viral control, but the identity and mechanisms regulating human antiviral B cells are unclear. Here, we characterized human B cells expressing T-bet and analyzed their dynamics during viral infections. T-bet+ B cells demonstrated an activated phenotype, a distinct transcriptional profile, and were enriched for expression of the antiviral immunoglobulin isotypes IgG1 and IgG3.

Corrigendum: Characterization of T-bet and Eomes in Peripheral Human Immune Cells.

[This corrects the article on p. 217 in vol. 5, PMID: 24860576.

Characterization of T-bet and eomes in peripheral human immune cells.

The T-box transcription factors T-bet and Eomesodermin (Eomes) have been well defined as key drivers of immune cell development and cytolytic function. While the majority of studies have defined the roles of these factors in the context of murine T-cells, recent results have revealed that T-bet, and possibly Eomes, are expressed in other immune cell subsets. To date, the expression patterns of these factors in subsets of human peripheral blood mononuclear cells beyond T-cells remain relatively uncharacterized.