A splice of life: the discovery, function, and clinical implications of FOXP3 isoforms in autoimmune disease.

Regulatory T cells (Tregs) are a specialized subset of CD4+ T cells essential for the maintenance of immune homeostasis and prevention of autoimmunity. Treg lineage and functions are programmed by the X-chromosome encoded transcription factor forkhead box P3 (FOXP3). In humans, multiple FOXP3 isoforms are generated through alternative splicing.

STAT3 signaling in B cells controls germinal center zone organization and recycling.

Germinal centers (GCs), sites of antibody affinity maturation, are organized into dark (DZ) and light (LZ) zones. Here, we show a B cell-intrinsic role for signal transducer and activator of transcription 3 (STAT3) in GC DZ and LZ organization. Altered zonal organization of STAT3-deficient GCs dampens development of long-lived plasma cells (LL-PCs) but increases memory B cells (MBCs).

B cell- and T cell-intrinsic regulation of germinal centers by thymic stromal lymphopoietin signaling.

Long-lived and high-affinity antibodies are derived from germinal center (GC) activity, but the cytokines that regulate GC function are still being identified. Here, we show that thymic stromal lymphopoietin (TSLP) signaling regulates the GC and the magnitude of antigen-specific antibody responses. Both GC B cells and T follicular helper (T) cells up-regulate the expression of surface TSLP receptor (TSLPR), but cell-specific loss of TSLPR results in distinct effects on GC formation and antibody production.

Regulation of B Cell Responses in SLE by Three Classes of Interferons.

There are three classes of interferons (type 1, 2, and 3) that can contribute to the development and maintenance of various autoimmune diseases, including systemic lupus erythematosus (SLE). Each class of interferons promotes the generation of autoreactive B cells and SLE-associated autoantibodies by distinct signaling mechanisms. SLE patients treated with various type 1 interferon-blocking biologics have diverse outcomes, suggesting that additional environmental and genetic factors may dictate how these cytokines contribute to the development of autoreactive B cells and SLE.

Context-Dependent miR-21 Regulation of TLR7-Mediated Autoimmune and Foreign Antigen-Driven Antibody-Forming Cell and Germinal Center Responses.

MicroRNAs (miRNAs) are involved in healthy B cell responses and the loss of tolerance in systemic lupus erythematosus (SLE), although the role of many miRNAs remains poorly understood. Dampening miR-21 activity was previously shown to reduce splenomegaly and blood urea nitrogen levels in SLE-prone mice, but the detailed cellular responses and mechanism of action remains unexplored. In this study, using the TLR7 agonist, imiquimod-induced SLE model, we observed that loss of miR-21 in mice prevented the formation of plasma cells and autoantibody-producing Ab-forming cells (AFCs) without a significant effect on the magnitude of the germinal center (GC) response.

Basophils and Eosinophils in Nematode Infections.

Helminths remain one of the most prolific pathogens in the world. Following infection helminths interact with various epithelial cell surfaces, including skin, lung, and gut. Recent works have shown that epithelial cells produce a series of cytokines such as TSLP, IL-33, and IL-25 that lead to the induction of innate and acquired type 2 immune responses, which we named Type 2 epithelial cytokines.

TLR7 Negatively Regulates B10 Cells Predominantly in an IFNγ Signaling Dependent Manner.

IL-10 producing B cells (B10 cells) play an important immunoregulatory role in various autoimmune and infection conditions. However, the factors that regulate their development and maintenance are incompletely understood. Recently, we and others have established a requirement for TLR7 in promoting autoimmune antibody forming cell (AFC) and germinal center (GC) responses.

Serine Phosphorylation of the STAT1 Transactivation Domain Promotes Autoreactive B Cell and Systemic Autoimmunity Development.

Although STAT1 tyrosine-701 phosphorylation (designated STAT1-pY701) is indispensable for STAT1 function, the requirement for STAT1 serine-727 phosphorylation (designated STAT1-pS727) during systemic autoimmune and antipathogen responses remains unclear. Using autoimmune-prone B6.Sle1b mice expressing a STAT1-S727A mutant in which serine is replaced by alanine, we report in this study that STAT1-pS727 promotes autoimmune Ab-forming cell (AFC) and germinal center (GC) responses, driving autoantibody production and systemic lupus erythematosus (SLE) development.

Type II but Not Type I IFN Signaling Is Indispensable for TLR7-Promoted Development of Autoreactive B Cells and Systemic Autoimmunity.

TLR7 is associated with development of systemic lupus erythematosus (SLE), but the underlying mechanisms are incompletely understood. Although TLRs are known to activate type I IFN (T1IFN) signaling, the role of T1IFN and IFN-γ signaling in differential regulation of TLR7-mediated Ab-forming cell (AFC) and germinal center (GC) responses, and SLE development has never been directly investigated. Using TLR7-induced and TLR7 overexpression models of SLE, we report in this study a previously unrecognized indispensable role of TLR7-induced IFN-γ signaling in promoting AFC and GC responses, leading to autoreactive B cell and SLE development.

B-Cell-Intrinsic Type 1 Interferon Signaling Is Crucial for Loss of Tolerance and the Development of Autoreactive B Cells.

Type 1 interferon (T1IFN) signaling promotes inflammation and lupus pathology, but its role in autoreactive B cell development in the antibody-forming cell (AFC) and germinal center (GC) pathways is unclear. Using a lupus model that allows for focused study of the AFC and GC responses, we show that T1IFN signaling is crucial for autoreactive B cell development in the AFC and GC pathways. Through bone marrow chimeras, DNA-reactive B cell transfer, and GC-specific Cre mice, we confirm that IFNαR signaling in B cells promotes autoreactive B cell development into both pathways.

Mer Receptor Tyrosine Kinase Signaling Prevents Self-Ligand Sensing and Aberrant Selection in Germinal Centers.

Mer tyrosine kinase (Mer) signaling maintains immune tolerance by clearing apoptotic cells (ACs) and inducing immunoregulatory signals. We previously showed that Mer-deficient mice (Mer) have increased germinal center (GC) responses, T cell activation, and AC accumulation within GCs. Accumulated ACs in GCs can undergo necrosis and release self-ligands, which may influence the outcome of a GC response and selection.

Cryo-EM maps reveal five-fold channel structures and their modification by gatekeeper mutations in the parvovirus minute virus of mice (MVM) capsid.

In minute virus of mice (MVM) capsids, icosahedral five-fold channels serve as portals mediating genome packaging, genome release, and the phased extrusion of viral peptides. Previous studies suggest that residues L172 and V40 are essential for channel function. The structures of MVMi wildtype, and mutant L172T and V40A virus-like particles (VLPs) were solved from cryo-EM data.

Spontaneous germinal centers and autoimmunity.

Germinal centers (GCs) are dynamic microenvironments that form in the secondary lymphoid organs and generate somatically mutated high-affinity antibodies necessary to establish an effective humoral immune response. Tight regulation of GC responses is critical for maintaining self-tolerance. GCs can arise in the absence of purposeful immunization or overt infection (called spontaneous GCs, Spt-GCs).

IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity.

Spontaneously developed germinal centers (GCs [Spt-GCs]) harbor autoreactive B cells that generate somatically mutated and class-switched pathogenic autoantibodies (auto-Abs) to promote autoimmunity. However, the mechanisms that regulate Spt-GC development are not clear. In this study, we report that B cell-intrinsic IFN-γ receptor (IFN-γR) and STAT1 signaling are required for Spt-GC and follicular T helper cell (Tfh cell) development.

Distinct and synergistic roles of FcγRIIB deficiency and 129 strain-derived SLAM family proteins in the development of spontaneous germinal centers and autoimmunity.

The inhibitory IgG Fc receptor (FcγRIIB) deficiency and 129 strain-derived signaling lymphocyte activation molecules (129-SLAMs) are proposed to contribute to the lupus phenotype in FcγRIIB-deficient mice generated using 129 ES cells and backcrossed to C57BL/6 mice (B6.129.RIIBKO).

B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance.

Signaling lymphocyte activation molecules (SLAMs) play an integral role in immune regulation. Polymorphisms in the SLAM family receptors are implicated in human and mouse model of lupus disease. The lupus-associated, somatically mutated, and class-switched pathogenic autoantibodies are generated in spontaneously developed germinal centers (GCs) in secondary lymphoid organs.

B cell-intrinsic TLR7 signaling is essential for the development of spontaneous germinal centers.

Spontaneous germinal center (Spt-GC) B cells and follicular helper T cells generate high-affinity autoantibodies that are involved in the development of systemic lupus erythematosus. TLRs play a pivotal role in systemic lupus erythematosus pathogenesis. Although previous studies focused on the B cell-intrinsic role of TLR-MyD88 signaling on immune activation, autoantibody repertoire, and systemic inflammation, the mechanisms by which TLRs control the formation of Spt-GCs remain unclear.

Decreased tumor progression and invasion by a novel anti-cell motility target for human colorectal carcinoma cells.

We have previously described a novel modulator of the actin cytoskeleton that also regulates Ras and mitogen-activated protein kinase activities in TGFβ-sensitive epithelial cells. Here we examined the functional role of this signaling regulatory protein (km23-1) in mediating the migration, invasion, and tumor growth of human colorectal carcinoma (CRC) cells. We show that small interfering RNA (siRNA) depletion of km23-1 in human CRC cells inhibited constitutive extracellular signal-regulated kinase (ERK) activation, as well as pro-invasive ERK effector functions that include phosphorylation of Elk-1, constitutive regulation of c-Fos-DNA binding, TGFβ1 promoter transactivation, and TGFβ1 secretion.

Adenosine A(2A) receptor activation limits chronic granulomatous disease-induced hyperinflammation.

Chronic granulomatous disease (CGD) is caused by defects in the NADPH oxidase complex and is characterized by an increased susceptibility to infection. Other significant complications of CGD include autoimmunity and non-infectious hyperinflammatory disorders. We show that a gp91(phox) deficiency leads to the development of phenotypically altered T lymphocytes in mice and that this abnormal, hyperactive phenotype can be modulated by activation of the adenosine A(2A) receptor.