Development of vaccines eliciting broadly neutralizing influenza antibodies (bnAbs) is an extraordinary challenge. One hypothetical proposal is that CD4+ T cell help to rare immuno-subdominant bnAb class memory B cells is one critical factor to cause these B cells to reenter secondary germinal centers (GCs) and generate potent bnAbs. In this regard, we previously showed that the prototypic hemagglutinin stem vaccine does not contain the dominant CD4+ T cell epitope. Here, to test the above hypothesis, we examined the effects of adding a single influenza T cell epitope to the stem vaccine in an influenza pre-infected booster mouse model. We found that this fused booster vaccine efficiently recruited anti-stem memory B cells with prior GC experience into the secondary GCs in draining lymph nodes. Furthermore, these secondary GC-experienced cells evolved, thereby contributing to generation of more potent neutralizing activity towards variant viruses. Thus, our results suggest the importance of T cell help in generating potent bnAbs by recruiting rare subdominant memory B cells into secondary GCs, and have implications for vaccine design.

Successive mRNA vaccinations preserve SARS-CoV-2-specific T-cell immunity, but how individual CD8⁺ T-cell clones behave across repeated booster doses and breakthrough infection (BTI) remains poorly defined. We longitudinally tracked bulk CD8⁺ TCRβ repertoires and spike-specific tetramer⁺ CD8⁺ T cells in adult participants across the third and fourth vaccine doses and subsequent BTI. Each booster continued to recruit previously unexpanded "new" responder clonotypes, but both the number and summed frequency of newly engaged clones declined with successive doses. In contrast, clones first recruited by the initial prime-boost doses-particularly those expanded after dose 2-formed a durable, hierarchically dominant memory pool that persisted for more than two years yet displayed progressively attenuated recall with later boosters. BTI revealed a complementary mode of repertoire remodeling: newly engaged clones that had not responded to prior vaccinations showed the strongest, but transient, expansion, broadening the antigenic targets beyond spike. On the other hand, vaccine-induced clones showed limited recall response while sustaining their dominance in the long term. Together, these findings indicate that repeated mRNA vaccination maintains a stable pool of early-established CD8⁺ T-cell clones but progressively limits their recall capacity, whereas BTI mobilizes additional, partially distinct clonotypes that expand robustly and broaden antigenic coverage.

Vaccines effectively stimulate protective immune responses in healthy individuals, but the precise roles of germinal center (GC) and follicular helper T (TFH) cells in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine responses are not fully understood. This study used a conditional loss-of-function mouse model to investigate antibody responses to the Wuhan spike protein, specifically eliminating newly developed TFH cells during either the primary or memory phase. Our findings demonstrated that TFH-mediated GC responses are essential for primary vaccination. However, after booster immunization, memory B-cell responses were effectively regulated through extrafollicular mechanisms, independent of TFH cells. Ablating IL-4 receptor signaling in B cells attenuated antibody production in both the primary and memory phases, highlighting the critical role of IL-4 for optimal humoral immunity. We identified a unique population of IL-4-expressing memory T (IL-4+Tm) cells, characterized by CD27, GATA3, and IRF4 expression, that is strongly associated with these extrafollicular memory B-cell responses, capable of neutralizing SARS-CoV-2 variants. Furthermore, Omicron-based booster immunization recovered the immunity against emerging variants under TFH-deficient conditions. These results suggest that IL-4+Tm cells are an alternative pathway to sustain memory responses when GC function is impaired, particularly in immunocompromised states. Our study advances the understanding of memory T-cell-mediated humoral responses to SARS-CoV-2, offering insights for future vaccine strategies.

Intracellular bacteria can survive in vivo, evading host immunity and antibiotics. Salmonella persists in organs such as spleen by invading in the phagocytic cells. However, it remains controversial which specific cell populations, e.g., macrophages, monocytes, neutrophils or dendritic cells, harbor the bacteria during persistent infection. To address this question, we employed a persistent infection mouse model using attenuated Salmonella expressing an acid tolerant fluorescent protein. We found that the bacteria predominantly resided in monocytes. Although these cells expressed Ly-6G, a typical marker for neutrophils, they did not exhibit a polymorphonuclear morphology. Furthermore, Salmonella primarily and preferentially invaded monocytes over other phagocytic cell types. Importantly, Salmonella was able to survive in monocytes even in the presence of antibiotics. Our findings demonstrate that monocytes serve as a critical survival niche for Salmonella in vivo, allowing the bacteria to evade both host immunity and antibiotics.

In early life, the immune and nervous systems are highly plastic and engage in complex, bidirectional communication that is critical for establishing postnatal immune tolerance, gut and brain development, and responses to environmental challenges. The developing gut microbiota exerts its influence on both systems via microbial metabolites to modulate immune responses and neural function. Early disruptions in the gut microbiota, in part due to preterm delivery or antibiotic treatment, are linked to long-term immune or neurodevelopmental impairments. In this review, we provide an overview of the current understanding how the microbiota crosstalk with immune cells regulates in the development and function of the nervous system.

Recent outbreaks of the ZIKA virus (ZIKV) in Brazil and Puerto Rico have been linked to an increase in the incidence of fetal microcephaly and Guillain-Barre syndrome. In addition, although a causal relationship remains unproven, ZIKV has been found in the brains of multiple sclerosis (MS) patients, prompting interest in a possible link. The present study aimed to elucidate the role of ZIKV in the pathogenesis of MS. ZIKV-infected mice with experimental autoimmune encephalomyelitis (EAE) exhibited aggravated EAE symptoms with significant demyelination of the central nervous system (CNS). Moreover, ZIKV infection promoted pathogenic T cell infiltration into the CNS by enhancing the expression of chemokines for C-C motif chemokine receptor 2 (CCR2) in astrocytes, which was dependent on TRAF6 signaling. Propagermanium, a CCR2 inhibitor, prevented ZIKV-induced exacerbation of EAE in mice. These findings highlight the critical role of TRAF6 signaling in the progression of neurological disorders caused by ZIKV infection.

Humanized mice are invaluable models for investigating human cell engraftment in vivo post-transplantation. Mice engrafted with human red blood cells (hRBCs) are useful for examining the physiological roles of hRBCs in vivo, including studies on blood disorders, immune responses, and transfusion-related research. These models hold promise for malaria infection studies and vaccine development. However, engrafted hRBCs in vivo in immunodeficient mice presents challenges that must be addressed to establish effective in vivo models. In this study, we explored the rejection mechanisms of hRBCs in immunodeficient NOD/Shi-scid-IL2rγnull (NOG) mice and developed a novel model for long-term RBC engraftment. We observed rapid depletion of fluorescent-labeled hRBCs in the liver, but not in other organs, of NOG mice, with Gr-1midCD68+ mouse macrophages play a significant role in the elimination of hRBCs in the liver. To counteract this, we created thymidine kinase (TK) transgenic (Tg) mice under the human CD68 promoter (NOG-pCD68-TK Tg), which, upon administration of valganciclovir (VGCV), led to the successful depletion of macrophages. Consequently, hRBCs showed significantly prolonged engraftment in NOG-pCD68-TK Tg mice compared to non-Tg mice following macrophage depletion, maintaining engraftment for up to 14 days post-transplantation. This study elucidates the erythrophagocytosis mechanisms of hRBCs in mice and establishes NOG-pCD68-TK Tg mice as a valuable model for the long-term engraftment of hRBCs, potentially advancing in vivo hRBC research.

Autoimmune sialadenitis is a hallmark of IgG4-related disease (IgG4-RD) and Sjögren syndrome (SS). The single-stranded RNA sensor TLR7 has been shown as a driver of sialadenitis. Although TLR7 is activated by ssRNA degradation products such as nucleosides and oligoribonucleotides, the role of these ligands in sialadenitis development remains unclear. Here, we demonstrate that lysosomal accumulation of endogenous nucleosides is sufficient to drive autoimmune sialadenitis. Loss-of-function genetic variations in the nucleoside transporter SLC29A3 cause lysosomal nucleoside accumulation, leading to constitutive activation of TLR7 and TLR8 in monocytes and macrophages. Consequently, macrophages infiltrate multiple organs in mice and humans. In Slc29a3‒/‒ mice, submandibular glands (SMGs) were impaired in saliva production. SLC29A3-deficiency specifically damaged Aqp5+ acinar and intercalated duct cells in SMGs, while sparing neighboring cells such as ductal and myoepithelial cells. Although macrophages accumulated in both the spleen and SMGs, lymphocyte infiltration and production of chemokines including CXCL9, CXCL13, and CCL5 occurred selectively in SMGs. In IgG4-RD patients, these chemokines were also produced in SMGs, highlighting parallels between sialadenitis in Slc29a3‒/‒ mice and IgG4-RD. These findings indicate that constitutive TLR7 activation by nucleosides is a key mechanism driving autoimmune sialadenitis.

The human gastrointestinal tract is a unique mucosal barrier with a tremendous surface area that is subject to continuous exposure to the environment. The immune system must remain poised to protect this organ system from potential pathogens while restraining chronic inflammatory responses that negatively impact physiological functions or facilitate malignancy. Innate lymphocytes emerged as major regulators of gut health through numerous key functions. Recent evidence indicates that these cells are adaptably influenced by specialized microniches, or distinct aggregates of cells that engage in dynamic crosstalk at a microscopic level and integrate signals from the environment to perform specialized functions with regional precision. Here we explore our current understanding of how microniches in the gut shape the biology of innate lymphocytes, with a focus on an interplay of diet and microbial exposure, selective cell-cell communication networks, and spatiotemporal properties. We also discuss how these microniches may be altered in human diseases or could be harnessed to better protect the gut. Finally, we identify current gaps in knowledge in this rapidly emerging field.