Eric M. Brown

Interactions between T cell receptors (TCRs), peptides, and human leukocyte antigens (HLAs) underlie antigen-specific T cell immunity. Despite substantial advances in prediction methods, accurate modeling of coupled TCR–peptide–HLA recognition remains underdeveloped, limiting applications such as TCR and neoepitope prioritization in cancer and antigen identification in autoimmunity. Here we present StriMap, a unified framework for predicting TCR–peptide–HLA interactions by integrating physicochemical, sequence-context, and structural features at recognition interfaces. StriMap achieves state-of-the-art performance with improved generalizability and enables applications in cancer and autoimmunity. As a case study, we screened 13 million peptides from 43,241 bacterial proteins and identified candidate molecular mimics that were experimentally validated to activate T cells expressing an ankylosing spondylitis (AS)-associated TCR. A top validated peptide was enriched in patients with inflammatory bowel disease (IBD), suggesting potential shared microbial triggers. Overall, StriMap provides a framework for rational immunotherapy design and dissecting antigenic drivers of autoimmunity.

Enteric neurons are essential regulators of intestinal physiology, yet their responses to varying microbial and immune environments along the intestinal tract and or during challenges remain poorly understood. In this study, we regionally profiled enteric neurons across gnotobiotic, allergic, and parasite-infected mice. Timing and complexity of microbial perturbations and type 2 inflammation result in motor neuron state shifts and alter multiple functionally distinct sensory neurons, including interleukin-13– and leukotriene-responsive Nmu -hi cells and Grp -hi neurons, which expand in germ-free colonic tissue and interact with Grpr ⁺ interstitial cells of Cajal. Leveraging adeno-associated virus–based Perturb-seq, we identified Edf1 and Mitf as controllers of motor neuron state transition and gastrointestinal transit time, directly linking enteric neuron states to physiology.

Plasma cells (PCs) constitute a significant fraction of colonic mucosal cells and contribute to inflammatory infiltrates in ulcerative colitis (UC). While gut PCs secrete bacteria-targeting IgA antibodies, their role in UC pathogenesis is unknown. We performed single-cell V(D)J- and RNA-seq on sorted B cells from the colon of healthy individuals and patients with UC. A large fraction of B cell clones is shared between different colon regions, but inflammation in UC broadly disrupts this landscape, causing transcriptomic changes characterized by an increase in the unfolded protein response (UPR) and antigen presentation genes, clonal expansion, and isotype skewing from IgA1 and IgA2 to IgG1. We also directly expressed and assessed the specificity of 152 mAbs from expanded PC clones. These mAbs show low polyreactivity and autoreactivity and instead target both shared bacterial antigens and specific bacterial strains. Altogether, our results characterize the microbiome-specific colon PC response and how its disruption might contribute to inflammation in UC.

Context shapes anticommensal immunity: The gut bacterium Akkermansia muciniphila is associated with protection from obesity, enhanced wound healing, and augmented antitumor responses. Ansaldo et al. found that this microbe induces antigen-specific immunoglobulin G1 (IgG1) antibodies generated by B cells with CD4 ⁺ T cell help. This is in contrast to most anticommensal responses, which involve the T cell–independent production of IgA antibodies. In a gnotobiotic setting in which all components of the microbiome are defined, A. muciniphila –specific T cells expanded only when A. muciniphila was present. The T cells primarily displayed a phenotype associated with B cell help. However, in mice with a conventional gut microbiota, other proinflammatory A. muciniphila –specific T cell populations also expanded. Thus, anti– A. muciniphila immunity is context dependent, which may explain the variable immune responses to this microbe reported in patients. Science , this issue p. 1179