Mast cells act as “signal converters,” translating immunological and tissue signals into host-protective behaviors. They sense antigen and possibly toxins driving avoidance behavior, which can prevent inflammation and tissue damage. Beyond classical immunity, mast cells rapidly activate antigen expulsion responses and initiate nociception. These reflexes promote host-protective behavior and maintain tissue integrity.

CD4+ T helper (Th) cell differentiation depends on regulatory networks that enforce lineage commitment while suppressing alternative fates. In a recent issue of Nature, Hou et al. reveal that calcitonin gene-related peptide (CGRP) directs Th1 commitment, highlighting neuro-immune crosstalk in T cell fate decisions.

Central tolerance restricts T cells that target self-antigens. In this issue of Immunity, Abdelfattah et al. describe a method to generate self-reactive T cell receptors (TCRs) by directed evolution of non-autoreactive TCRs to recognize self-antigen peptides and demonstrate potential for T cells engineered with such receptors in immunotherapy.

Hidradenitis suppurativa (HS) is a severe chronic inflammatory skin disease with limited response to therapy. In this issue of Immunity, Yu et al. identify skin tertiary lymphoid structures (TLSs) as primary sites for lymphocyte clonal expansion and autoantibody production, driving disease progression, and provide insight into how formation and maintenance of TLS impact therapeutic outcomes.

Despite protective roles in various type of infection and in would healing, T helper (Th)2 cells are drivers of inflammation in allergic asthma. In this issue of Immunity, Zou et al. demonstrate the crucial involvement of hypoxia inducible factor (HIF)2α in promoting the differentiation of inflammatory Th2 cells, suggesting HIF2α as a promising therapeutic target for the treatment of allergic asthma.

Inpp5d, which encodes the lipid phosphatase SHIP1, is a risk gene for Alzheimer’s disease, but its role in brain development has been poorly studied. Matera, Compagnion et al. demonstrate that Inpp5d is expressed in microglia during early postnatal brain development, where it limits synaptic pruning in a complement-dependent manner, and that its perturbation during brain development has long-lasting effects on cognitive function.

Immune activation is often thought to exacerbate stress-related mental disorders. Here, Xia, Lu, Lan, et al. reveal elevated IL-22 derived from the gut during the early phase of repeated stress. IL-22 suppresses neuron activation in the brain and mitigates stress-induced anxiety, suggesting an immune defense mechanism against psychological insults.