Issues

In this issue, Luff et al. 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.

Repeated tumor contact leaves more behind than simple CAR-T exhaustion. This study shows that chronic antigen exposure impairs a Rab5-dependent endocytic program, allowing trogocytosed antigen to accumulate, functional CAR to decline, and fratricide to increase.

In this issue of JEM, Liu et al. report PRECISE-seq, a proximity labeling platform that integrates T cell receptor specificity, functional potency, and cellular phenotype at a single-cell resolution. Using this approach, they identify an immunosuppressive Ly49⁺ T cell state within tumors that is alleviated by PD-1 blockade.

Human LCK deficiency syndromes demonstrate that T cell fate is set by signal amplitude, not molecular identity. This review synthesizes clinical observations with emerging views of thymic microenvironments to illuminate how TCR signal calibration shapes immunity and tolerance.

Kim et al. demonstrate that during enteric bacterial infection, mesentery-resident macrophages act as a regulatory hub that controls the recruitment of inflammatory monocytes with elevated pro-inflammatory cytokine expression, highlighting a critical role for the gut–mesentery axis in delaying progression to systemic infection.

Lyu et al. demonstrate that microbiota-specific RORγt⁺ regulatory T cells are uniquely restrained by B7 costimulation. Blocking B7, or signal two, promotes RORγt⁺ regulatory T cells and protects from intestinal inflammation, but only when acting in concert with MHCII-dependent signal one from RORγt⁺ antigen-presenting cells.

The chemokine CCL25 is expressed in the thymus and the small intestine. Li et al. show that thymic epithelial CCL25 facilitates T cell positive selection in the thymic cortex, whereas intestinal epithelial CCL25 promotes nutrient sensing in the small intestine. Epithelial CCL25 directs thymic T cell development and intestinal homeostasis in a tissue-specific paracrine manner.

Liu et al. develop PRECISE-seq, a single-cell platform linking TCR specificity and avidity to T cell phenotypes in vivo. They reveal that high-potency antiviral T cells become exhausted, while tumor-reactive CD8⁺ T cells acquire a regulatory Ly49⁺ state that is restrained by PD-1 blockade, resulting in effector revival within tumors.

Gu et al. show CAR T cell endocytic activity is lost after continuous tumor engagement. Introduction of Rab5 maintains functional CARs on the cell surface and removes trogocytosed tumor antigen, thereby improving the potency of CAR T cells.

Heavican et al. show that TET2 is an epigenetic regulator directing transcriptional reprogramming for T_FH cell differentiation, and long-term deficiency in CD4⁺ T cells deregulates self-renewal and skews differentiation, leading to the T_FH-derived lymphomagenesis. TET2 loss induces constitutive TCR and ICOS-PI3K activation. Clinical-grade demethylating agents enhance overall survival in Tet2^−/− murine models.

Fachi et al. identify LINGO4 as a key regulator of ILC3s, coordinating mitochondrial fitness and IL-22 production. LINGO4 deficiency disrupts ILC3 function and microbiota composition, altering susceptibility to enteric infections.

IBD involves the dysfunction of intestinal ILC3s. This study demonstrates that the transcription factor BACH2 maintains ILC3 function via PPARγ-mediated mitochondrial metabolism, thereby protecting against the development of IBD.

Luff et al. show that TACI, a BAFF and APRIL receptor related to BAFFR, is not a negative regulator of B cell survival as previously reported, but is required for the development of marginal zone B cells.

Humoral immune responses diversify over time but whether secreted antibodies influence this process is unknown. Using antibody secretion–deficient mice, this study shows a profound impact of secreted antibodies on the evolution of B cell diversity after vaccination.

He et al. identify AID as a key initiator of plasma cell differentiation, beyond its established roles in SHM and CSR. They show that AID cooperates with TET2 to initiate plasma cell commitment by promoting demethylation of the Irf4 locus.

This study shows that a secondary microglial expansion center has been identified in fetal brains with oSVZ.