Kira Rubtsova

Toll-like receptor 7 (TLR7)–driven accumulation of a novel CD11c + B-cell population is important for the development of autoimmunity

Females are more susceptible than males to many autoimmune diseases. The processes causing this phenomenon are incompletely understood. Here, we demonstrate that aged female mice acquire a previously uncharacterized population of B cells that we call age-associated B cells (ABCs) and that these cells express integrin α(X) chain (CD11c). This unexpected population also appears in young lupus-prone mice. On stimulation, CD11c(+) B cells, both from autoimmune-prone and healthy strains of mice, secrete autoantibodies, and depletion of these cells in vivo leads to reduction of autoreactive antibodies, suggesting that the cells might have a direct role in the development of autoimmunity. We have explored factors that contribute to appearance of ABCs and demonstrated that signaling through Toll-like receptor 7 is crucial for development of this B cell population. We were able to detect a similar population of B cells in the peripheral blood of some elderly women with autoimmune disease, suggesting that there may be parallels between the creation of ABC-like cells between mice and humans.

Crossreactive T cells spotlight the germline rules for αβ T cell receptor interactions with MHC molecules

To test whether highly crossreactive alphabeta T cell receptors (TCRs) produced during limited negative selection best illustrate evolutionarily conserved interactions between TCR and major histocompatibility complex (MHC) molecules, we solved the structures of three TCRs bound to the same MHC II peptide (IAb-3K). The TCRs had similar affinities for IAb-3K but varied from noncrossreactive to extremely crossreactive with other peptides and MHCs. Crossreactivity correlated with a shrinking, increasingly hydrophobic TCR-ligand interface, involving fewer TCR amino acids. A few CDR1 and CDR2 amino acids dominated the most crossreactive TCR interface with MHC, including Vbeta8 48Y and 54E and Valpha4 29Y, arranged to impose the familiar diagonal orientation of TCR on MHC. These interactions contribute to MHC binding by other TCRs using related V regions, but not usually so dominantly. These data show that crossreactive TCRs can spotlight the evolutionarily conserved features of TCR-MHC interactions and that these interactions impose the diagonal docking of TCRs on MHC.

Genetic and hormonal factors in female-biased autoimmunity

Autoimmunity is controlled both by the environment and by genetic factors. One of the most well defined genetic factors is polymorphisms, with some alleles of particular genes promoting autoimmune diseases, whereas other alleles either not affecting susceptibility to disease or, in some cases actually inhibiting the appearance of such illnesses. Another genetically controlled factor, gender, also plays a profound role in the incidence of autoimmune diseases. For example, Systemic Lupus Erythematosus (SLE) occurs much more frequently in females than in males in both mice and man. The genetic differences that make some individuals susceptible to autoimmunity and protect others could act in many ways and affect many tissues. In this review we will discuss how gender may act on the cells of the immune system and thereby influence the predisposition of the host to autoimmune diseases.

T-box transcription factor T-bet, a key player in a unique type of B-cell activation essential for effective viral clearance

Significance Here, we show that signals delivered by antigen engagement, IFNγ, and toll-like receptor 7 [TLR7] induce T-box transcription factor T-bet and IgG2a switching in B cells. The IgG2a product of these signals is important for viral immunity. For example, the titers of mouse gammaherpesvirus 68, an Epstein–Barr-related virus, are not well reduced if the B cells cannot express T-bet and consequently cannot switch to production of IgG2a. The T-bet expressing B cells resemble a subset of B cells that appears in autoimmune prone mice and women. Thus, a B-cell differentiation pathway that has evolved to promote immunity to viruses may also contribute to autoimmunity. IgG2a is known to be the most efficient antibody isotype for viral clearance. Here, we demonstrate a unique pathway of B-cell activation, leading to IgG2a production, and involving synergistic stimulation via B-cell antigen receptors, toll-like receptor 7 (TLR7), and IFNγ receptors on B cells. This synergistic stimulation leads to induction of T-box transcription factor T-bet expression in B cells, which, in turn, drives expression of CD11b and CD11c on B cells. T-bet/CD11b/CD11c positive B cells appear during antiviral responses and produce high titers of antiviral IgG2a antibodies that are critical for efficient viral clearance. The results thus demonstrate a previously unknown role for T-bet expression in B cells during viral infections. Moreover, the appearance of T-bet+ B cells during antiviral responses and during autoimmunity suggests a possible link between these two processes.

Sexual dimorphism in autoimmunity

Autoimmune diseases occur when the immune system attacks and destroys the organs and tissues of its own host. Autoimmunity is the third most common type of disease in the United States. Because there is no cure for autoimmunity, it is extremely important to study the mechanisms that trigger these diseases. Most autoimmune diseases predominantly affect females, indicating a strong sex bias. Various factors, including sex hormones, the presence or absence of a second X chromosome, and sex-specific gut microbiota can influence gene expression in a sex-specific way. These changes in gene expression may, in turn, lead to susceptibility or protection from autoimmunity, creating a sex bias for autoimmune diseases. In this Review we discuss recent findings in the field of sex-dependent regulation of gene expression and autoimmunity.

Age-Associated B Cells: A T-bet-Dependent Effector with Roles in Protective and Pathogenic Immunity.

A newly discovered B cell subset, age-associated B cells, expresses the transcription factor T-bet, has a unique surface phenotype, and accumulates progressively with age. Moreover, B cells with these general features are associated with viral infections and autoimmunity in both mice and humans. In this article, we review current understanding of the characteristics, origins, and functions of these cells. We also suggest that the protective versus pathogenic actions of these cells reflect appropriate versus aberrant engagement of regulatory mechanisms that control the Ab responses to nucleic acid–containing Ags.

CD11c-Expressing B Cells Are Located at the T Cell/B Cell Border in Spleen and Are Potent APCs

In addition to the secretion of Ag-specific Abs, B cells may play an important role in the generation of immune responses by efficiently presenting Ag to T cells. We and other investigators recently described a subpopulation of CD11c+ B cells (Age/autoimmune-associated B cells [ABCs]) that appear with age, during virus infections, and at the onset of some autoimmune diseases and participate in autoimmune responses by secreting autoantibodies. In this study, we assessed the ability of these cells to present Ag and activate Ag-specific T cells. We demonstrated that ABCs present Ag to T cells, in vitro and in vivo, better than do follicular B cells (FO cells). Our data indicate that ABCs express higher levels of the chemokine receptor CCR7, have higher responsiveness to CCL21 and CCL19 than do FO cells, and are localized at the T/B cell border in spleen. Using multiphoton microscopy, we show that, in vivo, CD11c+ B cells form significantly more stable interactions with T cells than do FO cells. Together, these data identify a previously undescribed role for ABCs as potent APCs and suggest another potential mechanism by which these cells can influence immune responses and/or the development of autoimmunity.

JAK-STAT signaling pathways are activated in the brain following reovirus infection

Reovirus infection provides a classic experimental model system for studying the pathogenesis of viral infections of the central nervous system (CNS), with apoptosis acting as the major mechanism of cell death. The authors have examined the role of signal transducer and activator of transcription (STAT)1, a component of Janus-activated kinase (JAK)-STAT signaling, a pathway implicated in antiviral responses and pathways regulating apoptosis, following reovirus infection. Infection of primary cortical neuron cultures with reovirus serotype 3 strain Abney (T3A) resulted in phosphorylation of STAT1 at sites critical for transcriptional activity. Activated STAT1 was also detected in the brain of neonatal mice following T3A infection, with a nuclear pattern of expression in areas of virus-induced injury. Activation of STAT proteins is typically mediated by JAKs. The authors observed JAK2 phosphorylation (Tyr 1007/1008) in brain lysates from T3A-infected mice. Inhibition of JAK activity with the inhibitor AG-490 blocked reovirus-induced STAT1 activation in neuronal cultures, indicating reovirus-induced STAT activation is JAK dependent. Pretreatment of neuronal cultures with antibody raised against interferon (IFN)-α/βR2 inhibited T3A-induced STAT1 phosphorylation, whereas neither IFN-γ or IFN-γR2 antibody pretreatment had any effect on T3A-induced STAT1 phosphorylation. Mice lacking the STAT1 gene demonstrated increased susceptibility to reovirus infection, with increased mortality and higher viral titers in the brain compared to wild-type animals. The results demonstrate activation of a type I IFN-mediated, JAK-dependent STAT signaling pathway following reovirus infection and suggest that STAT1 is a key component of host defense mechanisms against reovirus infection in the brain.

Many different Vβ CDR3s can reveal the inherent MHC reactivity of germline-encoded TCR V regions

We have hypothesized that in the prenegative selection TCR repertoire, many somatically generated complementary-determining region (CDR) 3 loops combine with evolutionarily selected germline Vα/Vβ CDR1/CDR2 loops to create highly MHC/peptide cross-reactive T cells that are subsequently deleted by negative selection. Here, we present a mutational analysis of the Vβ CDR3 of such a cross-reactive T-cell receptor (TCR), YAe62. Most YAe62 TCRs with the mutant CDR3s became less MHC promiscuous. However, others with CDR3s unrelated in sequence to the original recognized even more MHC alleles than the original TCR. Most importantly, this recognition was still dependent on the conserved CDR1/CDR2 residues. These results bolster the idea that germline TCR V elements are inherently reactive to MHC but that this reactivity is fine-tuned by the somatically generated CDR3 loops.

B cells expressing the transcription factor T-bet drive lupus-like autoimmunity

B cells contribute to multiple aspects of autoimmune disorders and may play a role in triggering disease. Thus, targeting B cells may be a promising strategy for treating autoimmune disorders. Better understanding of the B cell subsets that are responsible for the development of autoimmunity will be critical for developing efficient therapies. Here we have reported that B cells expressing the transcription factor T-bet promote the rapid appearance of autoantibodies and germinal centers in spontaneous murine models of systemic lupus erythematosus (SLE). Conditional deletion of T-bet from B cells impaired the formation of germinal centers and mitigated the development of kidney damage and rapid mortality in SLE mice. B cell–specific deletion of T-bet was also associated with lower activation of both B cells and T cells. Taken together, our results suggest that targeting T-bet–expressing B cells may be a potential target for therapy for autoimmune diseases.