Andrea Cerutti

This review discusses evidence indicating that the human nasopharyngeal mucosa includes a heterogeneous subset of memory B cells expressing IgD but not IgM. Such IgD ⁺ IgM ⁻ memory (IgD‐ME) B cells differentiate from germinal center B cell precursors that have undergone class switching from IgM to IgD in tonsillar lymphoid follicles. This DNA recombination process is associated with a mutation‐intensive program aimed at generating broadly reactive IgD antibodies that target a vast array of microbial and non‐microbial antigens. We review data indicating that many IgD‐ME B cells express atypical‐like B cell properties, accumulate polyreactivity and some autoreactivity in a somatic hypermutation‐dependent manner, and include precursors of IgD‐secreting IgD ⁺ IgM ⁻ plasma cells (IgD‐PCs). We further discuss the complex innate and adaptive signaling networks underlying the induction of IgD‐ME B cells and their clonal differentiation into IgD‐PCs. Furthermore, we consider the broad reactivity and functional effects of the IgD antibodies expressed by IgD‐ME B cells and released by IgD‐PCs. Moreover, we delve into the mechanisms whereby secreted IgD antibodies may contribute to mucosal tolerance and homeostasis. Lastly, we examine human disorders associated with abnormalities of the IgD response.

Effector T lymphocytes are avid nutrient consumers, but can function in nutrient-poor tumor microenvironments. Availability of key nutrients such as glucose inside the tumor is not homogeneous, and how tumor-infiltrating T lymphocytes (TILs) differ between regions with better and poorer blood perfusion is not well known. Here we show that in vitro-stimulated TILs can induce substantial production of hallmark glucose-dependent cytokines under glucose concentrations 20 times lower than in blood. In vivo, effector TILs in tumor regions with poor access to blood show comparable capacity for inducing IFNγ and granzyme B to TILs with fuller accessibility; exhibit an enhanced type I IFN response supported by local myeloid cells; and unexpectedly, have reduced expression of immune checkpoint and Treg-associated markers. TILs with poor blood accessibility also have lower biosynthetic activity than highly blood-accessible TILs, yet both compartments depend fundamentally on glucose for ATP production. Thus, effector T lymphocytes in poorly perfused tumor regions can maintain specific glucose-dependent responses, and might be partially protected from inhibitory and exhausting pressure from the tumor microenvironment.

In this issue, Luff et al. (https://doi.org/10.1084/jem.20251308) show that cell-intrinsic signals from TACI drive marginal zone B cell development from T2 B cells through a mechanism involving activation of the PI3K–AKT pathway and inhibition of the FOXO1-KLF2 axis.

Human tonsils from the nasopharyngeal mucosa mount frontline antibody responses, including IgD secretion by IgD+IgM– plasma cells (IgD-PCs). The developmental origins and functional significance of these IgD responses remain poorly understood. Here, we show that most IgD-PCs clonally emerge from a heterogeneous population of IgD class-switched IgD+IgM– memory (IgD-ME) B cells that reside within the epithelial, subepithelial, and interfollicular areas of the nasopharyngeal mucosa and share transcriptional and phenotypic properties with atypical B cells. These IgD-ME B cells arise from a mutation-intensive pathway that involves integrated innate and adaptive signals and engenders reactivities to respiratory commensal bacteria, common environmental antigens, and allergens. Such reactivities weaken in germline IgD revertants. Thus, the secreted IgD response heavily relies on nasopharyngeal mucosal IgD-ME B cells via a germinal center–imprinted mutational program that presumably enhances mucosal homeostasis and environmental tolerance.

Extramedullary organs such as the spleen can assume granulopoiesis as a supportive mechanism to cope with increased demands during persistent inflammation. However, the quantitative output of extramedullary granulopoiesis is limited, and whether the spleen provides neutrophils of a qualitative difference remains unclear. Here, we found that splenic stress granulopoiesis is associated with distinct neutrophil production and differentiation trajectories. Myeloid progenitors in the spleen engaged in accelerated production of neutrophils with an immature phenotype. Yet, neutrophils generated during persistent stress granulopoiesis were fully competent to exert antimicrobial functions and were necessary to contain bacterial invasion in the bladder. Activation of type I interferon signaling in the spleen was required for splenic neutrophil priming, and its loss impaired antibacterial host defense. Thus, the spleen provides an immunological environment for stress-induced rapid production and priming of highly active neutrophils to meet demands during infection.

The gut microbiota enhances systemic immunoglobulin G (IgG) responses to vaccines, but it is unknown whether this effect involves IgA, which coats intestinal microbes. That IgA may amplify postimmune IgG production is suggested by the impaired IgG response to pneumococcal vaccines in some IgA-deficient patients. Here, we found that antipneumococcal but not total IgG production was impaired in mice with IgA deficiency. The positive effect of gut IgA on antipneumococcal IgG responses started very early in life and could implicate gut bacteria, as these responses were attenuated in germ-free mice recolonized with gut microbes from IgA-deficient donors. IgA could exert this effect by constraining the systemic translocation of gut antigens, which was associated with chronic immune activation, including T cell overexpression of programmed cell death protein 1 (PD-1). This inhibitory receptor may attenuate antipneumococcal IgG production by causing B cell hyporesponsiveness, which improved upon anti–PD-1 treatment. Thus, gut IgA functionally interacts with systemic IgG to enhance antipneumococcal vaccine responses.