Nature Immunology

Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is traditionally framed within a dichotomy of health and disease, yet its systemic immune consequences across the spectrum of CFTR activity remain incompletely defined. Using multimodal immune profiling, we constructed a single-cell atlas of circulating immune cells in people with cystic fibrosis (pwCF), healthy F508del carriers and non-carriers. In pwCF, circulating immunity was markedly altered following treatment with elexacaftor-tezacaftor-ivacaftor, with broad reductions in pro-inflammatory cytokines and immune changes linked to improved clinical outcomes. Strikingly, healthy F508del carriers exhibited a CF-like immune signature characterised by low-grade systemic inflammation, including elevated IL-6, reduced mucosal-associated invariant T cells, and inflammatory monocyte features overlapping with pwCF. Together, these findings show that CFTR dysfunction spans a spectrum of systemic immune dysregulation, challenging a strict dichotomy between health and disease.

Fibroblasts play a dual role in shaping tissue homeostasis and immune responses during inflammatory perturbations. Manipulating fibroblast behavior has therefore emerged as a promising strategy for autoimmune diseases. Here, through integrated multimodal single-cell transcriptomic and proteomic profiling of synovial tissue combined with prospective clinical data from 54 patients with rheumatoid arthritis, we identify C-X-C motif chemokine 12 (CXCL12)hi Apolipoprotein C1 (APOC1)+ fibroblasts as a pathogenic cell population driving refractory synovitis. CXCL12hi APOC1+ fibroblasts construct local niche in spatial coordinates with plasmablasts via the CXCL12-CXCR4 axis. APOC1 orchestrates senescent inflammatory cancer-associated fibroblast(iCAF)-like properties of this cluster through activation of the STAT3-C/EBP pathway. Therapeutic elimination of senescent cells, either alone or in combination with TNF inhibition, significantly ameliorates experimental arthritis. Together, these findings uncover a mechanistic basis for treatment resistance in rheumatoid arthritis and highlight senescent iCAF-like fibroblasts as a promising therapeutic target.

Chronic forms of autoimmune arthritis, including juvenile idiopathic arthritis (JIA), are characterised by persistent synovial inflammation. While adaptive mechanisms are well-studied, the innate networks driving early joint disease remain poorly defined. Here, through unbiased profiling of innate lymphoid cells from JIA joints at disease onset, we identify activated natural killer (NK) cells as key orchestrators of adaptive immune niches. The selective upregulation of lymphotactin (XCL1) by activated NK cells is accompanied by the synovial enrichment of XCR1+ type 1 conventional dendritic cells (cDC1s), directly correlating with disease severity. In situ, NK cells spatially anchor with recruited cDC1s to assemble discrete, multicellular effector niches alongside T cells. Finally, we demonstrate this NK-cDC1 spatial architecture represents a conserved pathogenic module across adult arthropathies, including rheumatoid arthritis. Our findings establish the XCL1-XCR1 axis as a fundamental innate feature of chronic joint inflammation, defining a targetable mechanism that precedes and promotes downstream adaptive responses.

Immunological memory depends on the maintenance of stem cell-like memory CD8 T cells, which require sustained expression of the transcription factors TCF1. Here, I identify MLL1 as a key regulator of CD8 T cell memory. In activated T cells, MLL1 sustains Tox transcription through interaction with MENIN, thereby maintaining BTLA expression and restraining cytokine-driven AKT activation. Loss of MLL1 or disruption of the MLL1-MENIN interaction accelerates AKT-driven loss of TCF1, leading to impaired memory potential. MLL1-deficient T cells fail to reconstitute lymphopenic hosts and are unable to mediate graft-versus-host disease, while exhibiting increased expansion of virtual memory T cells. Unexpectedly, MLL1 regulates Tox, Btla and Tcf7 independently of its methyltransferase activity and MOF-mediated H4K16 acetylation. These findings define a pathway in which the MLL1-MENIN complex restrains cytokine signaling to preserve CD8 T cell memory and identify a noncanonical function of MLL1 in transcriptional maintenance.

Caspases-mediated processing of cytokines coordinates cell-autonomous defenses and induction of systemic inflammation 1. While caspase-1 processes IL-1{beta} and IL-18 2-5, human caspase-4 processes IL-18 mainly in monocytes 6. Caspase-14 is an exception, specializing in epidermal differentiation7,8, yet no cytokine target has been firmly established for caspase-14. Here, we report that recognition and IL-1{beta} maturation of IL-1{beta} by caspase-14 in epithelial cells determined anti-bacterial humoral immunity against Yersina pseudotuberculosis (Y. pseudotuberculosis) infection. Upon TAK1 inhibition by YopJ, activated caspase-8 cleaved caspase-14 at Asp 146, generating an active 16-kDa fragment, whose exposed pocket directly interacted with and cleaves pro-IL-1{beta} at Cys132. Moreover, conditional knock-out of caspase-14 in epithelial cells or knock-in of a caspase-inactive caspase-14C136A mutant impaired Y. pseudotuberculosis induced IL-1{beta} production and eliminated the total anti-Y. pseudotuberculosis IgG production, leading to uncontrolled Y. pseudotuberculosis infection. Thus, our findings establish caspase-14 as a processor of IL-1{beta} in epithelial cells to propel anti-bacterial humoral immunity, providing insights into the inflammation and vaccine development.

The immune system consists of diverse cell types that act in coordination, yet it remains unclear at what biological scale coherent immune organization emerges. Here we analyze single-cell transcriptomics from a large longitudinal cohort of healthy adults and demonstrate that transcription is coordinated across immune cells. Although baseline expression differs by cell type, transcriptional deviations spanning thousands of genes align across immune cells within donors. This alignment resolves into axes of transcriptional variation that organize both inter-donor differences and longitudinal change. Leading axes capture the largest fraction of variance and reflect dynamic shifts shared across donors, whereas higher-order axes encode more stable donor-specific structure. We refer to this shared multi-dimensional variance structure as the immune transcriptional landscape (ITL). An individuals position within the ITL reflects their transcriptional configuration and is recapitulated in matched serum proteomics, linking immune cell transcription to the circulating proteome. Together, these findings demonstrate that coherent immune organization is encoded in coordinated gene expression across immune cells, revealing a multi-dimensional, temporally stratified transcriptional landscape shared across individuals and over time.

Genome-wide association studies have identified thousands of variants associated with immune-related diseases, yet most lie in non-coding regions, complicating mechanistic interpretation. Regulatory quantitative trait loci (QTLs), such as expression QTLs (eQTLs) and chromatin accessibility QTLs (caQTLs), offer a powerful framework for prioritization and interpretation of these disease-associated genetic variants. When analyzed together, they offer deeper insights into the regulatory architecture underlying disease. We generated same-cell, single-cell multi-omics data, integrating transcriptomic and chromatin accessibility information, from 563,100 matched peripheral blood mononuclear cells collected from 264 individuals, either unstimulated or stimulated for 24h with C. albicans (CA). Across six major immune cell types, we mapped both cis-eQTLs and -caQTLs, identifying 1,571 eGenes and 28,862 caPeaks, with 41% and 11% showing a stimulation-dependent effect. Finally, to dissect the regulatory mechanisms underlying these QTL effects, we applied two complementary strategies: 1. overlapping caQTLs with eQTLs; 2. applying SCENIC+ to identify regulatory triplets containing a transcription factor, the chromatin region it may bind to and the candidate target genes it thereby may regulate. With the first approach, we identified 1,861 dual-acting QTLs. These dual-QTLs showed 1.9-fold stronger enrichment for immune-related disease associations than single-modality QTLs, highlighting their relevance for disease interpretation. With the second approach, we found 62,932 regulatory triplets, of which 1.7% were under genetic control. By then leveraging the SCENIC+-derived TF activity measurements we could study how genetic variants can rewire TF control of gene expression, ultimately shaping inter-individual variation in disease risk. Together, our network-based approach offers new insights into the cellular contexts and gene programs perturbed in disease, providing a foundation for prioritizing therapeutic targets and informing strategies for disease prevention.

Interleukin-1 (IL-1) is a central driver of autoinflammatory disease, yet IL-1 blockade often provides incomplete benefit in complex, neutrophil-driven conditions. Here we identify a licensing circuit in which common {gamma}-chain ({gamma}c) cytokines provide a redundant signal required for maximal IL-1-driven neutrophil inflammation. IL-1 and {gamma}c cytokines synergize to drive inflammatory cytokine production exceeding either stimulus alone, and these signals engage the MEK/ERK pathway, an effect substantially suppressed by pharmacological MEK inhibition. We validated this circuit in vivo in a mouse model of IL-1-driven neutrophil-dominant autoinflammation. Ablation of the shared {gamma}c receptor markedly prolonged survival and attenuated pathology, whereas deletion of individual {gamma}c cytokine pathways had no major effect--demonstrating in vivo necessity and functional redundancy. Analysis of public phospho-proteomic and transcriptomic datasets confirms MEK/ERK as a conserved neutrophil response to diverse inflammatory stimuli and coordinated IL-1, {gamma}c, and MEK/ERK activation in neutrophils from patients with systemic juvenile idiopathic arthritis (sJIA) and in lesional skin from hidradenitis suppurativa. Together, these findings define a signaling architecture in which redundant {gamma}c inputs enhance MEK/ERK-dependent inflammatory output, identify the {gamma}c receptor as an in vivo disease-modifying node, and position MEK/ERK as a mechanistically grounded therapeutic target. eTOC SummaryLorenzo et al. show that common {gamma}-chain ({gamma}c) cytokines provide redundant licensing signals that amplify IL-1-driven neutrophil inflammation through MEK/ERK convergence. Blocking any single {gamma}c cytokine fails to suppress disease, but ablating the shared {gamma}c receptor or inhibiting MEK/ERK markedly attenuates pathology, identifying these nodes as therapeutic targets in autoinflammatory disease.

Pulmonary hemorrhage (PH) is a life-threatening manifestation of systemic autoimmunity characterized by immune-mediated disruption of the alveolar-capillary barrier. Despite mortality rates exceeding 50%, the molecular checkpoints that govern the transition from destructive inflammation to protective immune regulation remain poorly defined. Building on our discovery that interleukin-2-inducible T cell kinase (ITK) uncouples pathogenic inflammation from protective immunity, we investigated ITK as a central regulator of autoimmune lung injury. Using the pristane-induced PH model, we show that ITK deficiency confers near-complete protection against PH and associated multi-organ injury. This protection is accompanied by marked remodeling of the T cell compartment, including expansion of CD44CD122EomesT-bet memory-like subsets and significant enrichment of Foxp3 regulatory T cells (Tregs). Notably, adoptive transfer of ITK-deficient Tregs was sufficient to rescue PH and suppress systemic proinflammatory cytokine production in wild-type recipients, identifying these cells as key mediators of tissue protection. Transcriptomic profiling further revealed that loss of ITK signaling reprograms Tregs toward a metabolically and functionally enhanced state, with enrichment of oxidative phosphorylation (OXPHOS), mTORC1, STAT5 signaling, and tissue-repair-associated programs. Together, these findings identify ITK as a critical regulator of the balance between pulmonary injury and reparative immunity and provide a mechanistic rationale for targeting the ITK axis in severe inflammatory lung disease. HighlightsO_LIITK deficiency protects against pristane-induced pulmonary hemorrhage (PH) C_LIO_LILoss of ITK expands "super-fit" canonical and non-canonical Tregs C_LIO_LIITK-deficient Tregs exhibit enriched mTORC1, OXPHOS, and IL-10 production C_LIO_LITransfer of ITK-deficient Tregs rescues established PH and reverses proteinuria C_LIO_LIITK uncouples pathogenic inflammation from reparative tissue immunity C_LI

CD4 T cells are orchestrators of the immune system with diverse effector functions. Their full molecular diversity remains unclear due to the lack of a unified framework. Within the immgenT project, we profiled RNA, surface markers, and TCR clonotypes in conventional CD4T cells across >700 samples. Integration with a joint RNA-protein deep generative model revealed an ensemble of 20 CD4 states that account for all cells across tissues and challenges. Small, highly polarized clusters ("tips") that evoke Th1, Th2, Th17, and Tfh states co-exist with a majority of activated cells with mixed programs occupying "midland" states. Unlike CD8 T cells, memory CD4 cells largely mapped to the same states as effectors. Resting states proved quite diverse, and we uncovered unexpected similarities between Tfh and chronically-stimulated states. Together, immgenT provides a unified molecular reference for CD4 T cell diversity.

The oral mucosa is a prototypical human barrier reliant on neutrophils for homeostasis, as both neutrophil deficiency and excessive activation are linked to immunopathology. Yet, whether neutrophils acquire tissue-specific states in health or disease remains unclear. We incorporated single-cell RNA sequencing, spectral flow cytometry, and spatial proteomics across tooth-associated oral mucosa (gingiva) and interconnected compartments of blood and oral cavity to define neutrophil tissue specification in healthy individuals and patients with periodontitis, a neutrophil-dominated inflammatory disease. In health, mucosal neutrophils adopt discrete immunoregulatory states despite constant microbial exposure and mechanical injury. Periodontitis disrupts these programs through infiltration of blood-like neutrophil subsets, increased transcriptional noise, and heightened effector activation. Strikingly, oral inflammation systemically imprints on circulating neutrophils, marked by the expansion of a Rho-GTPase regulatory program that is shared across diverse human inflammatory conditions. Together, these findings establish a framework for understanding how localized tissue inflammation affects both neutrophil plasticity at barrier surfaces and conditioning of systemic neutrophil states with broad implications for inflammatory disease pathogenesis.

The immune system is a dynamic network of diverse cell types distributed across tissues. While mouse studies have highlighted the importance of tissue-localized B-cell responses in infection and tissue repair, research on human B cells has remained largely confined to peripheral blood. Here, we specifically investigated the human B-cell compartment and its interactions with the immune microenvironment across 10 tissues, using single-cell RNA sequencing and paired B-cell receptor sequencing. We mapped the full spectrum of B-cell populations and revealed diverse differentiation trajectories spanning naive, memory, and plasma cell types. Germinal center B cells and plasma cells showed tissue-specific adaptations in transcriptional states, isotype usage, and functional profiles. Plasma cell isotypes influenced both effector functions and predicted interactions with T cells. Finally, we defined tissue-specific residency gene modules that outperformed existing memory B-cell signatures. Together, this dataset serves as a foundation for systematically studying tissue-localized B cells and reveals how local microenvironments shape humoral immunity.

Gene expression in regulatory T cells (Tregs) is context-dependent and maintains peripheral immune homeostasis. FOXP3 is lineage defining but not sufficient for Treg function or persistence. To define the cell-intrinsic roles of the FOXP3 paralogs FOXP1 and FOXP4, we generated and studied mice with Treg-specific deletion of Foxp1 and/or Foxp4. FOXP1 and FOXP4 are required to maintain the peripheral Treg pool through enhancing Il2ra transcription, thereby promoting sustained high-level expression of IL-2R and thus of the high-affinity IL-2R{beta}{gamma} complex. Integrating RNA-seq and ATAC-seq with previously published ChIA-PET and publicly available data, we propose a model of Il2ra transcriptional regulation in which in which FOXP1 and FOXP4 anchor chromatin looping of the Il2ra locus in mature Tregs, augment super-enhancer activity, and drive sustained CD25 expression. Our results reveal a unique role of FOXP1, and to a lesser extent FOXP4, in controlling Treg homeostasis. One Sentence SummaryFOXP1 and FOXP4 regulate chromatin architecture at the Il2ra locus, promoting sustained CD25 expression and maintaining the peripheral Treg pool.

Tumor-reactive T cells (TRTs) are critical for anti-tumor immunity but are incompletely captured by current assays, which fail to reproduce tumor-specific antigen diversity. Here, we show that multiplex functional profiling of patient-derived tumor organoid-T cell co-cultures (PDOTs) enables robust identification of TRTs across CD8, CD4, and double-negative (DN) T cell populations. Single activation markers underestimated TRT responses, whereas integrated analysis revealed broader functional repertoire. MHCI blockade abrogated CD8 and DN TRT responses while preserving CD4 reactivity, supporting antigen-dependent recognition across T cell lineages. Tumor PDO expressed MHCI and MHCII, and PDOTs enabled generation and detection of TRTs from peripheral blood. PD1 blockade induced heterogeneous responses, enhancing CD8 and DN activity and unexpectedly augmenting CD4 reactivity. PDOTs further identified additional inhibitory pathways whose therapeutic targeting in combination with PD1 blockade increased TRT responses. These findings establish PDOTs as a platform to identify TRTs and functionally stratify patient-specific tumor-T cell responses to checkpoint immunotherapy.

The intestinal epithelium plays a pivotal role in balancing immune tolerance and inflammation, yet how it communicates tissue state to the adaptive immune system remains unclear. Here, we show that intestinal epithelial cells (IECs) encode tissue identity and injury into the major histocompatibility complex class II (MHC II) ligandome. We employed integrated single cell transcriptomics, quantitative proteomics, and high-depth in vivo immunopeptidomics to map the MHC class II self-peptidome of the mouse small intestine across epithelial and immune compartments. Mature enterocytes and intestinal stem cells (ISCs) emerged as the dominant epithelial antigen-presenting cells (APCs), displaying a compartmentalized repertoire of endogenous self-immunopeptides reflecting epithelial differentiation and function. Disruption of epithelial MHC II expression led to loss of antigenic compartmentalization, immune infiltration, extracellular matrix remodeling, and emergence of inflammation-associated immune ligands, demonstrating that epithelial MHC II is required to maintain homeostasis. Functionally, a subset of ISC-derived self-immunopeptides preferentially promotes regulatory CD4{square} T cell responses, linking epithelial antigen presentation and peripheral tolerance. During gut inflammation, the epithelial MHC II landscape shifted toward damage-associated antigens. Together, these findings establish epithelial MHC II presentation as a context-dependent tissue-immune communication system that promotes tolerance in homeostasis and alerts to tissue injury during inflammation.

Juvenile dermatomyositis (JDM) is characterized by a type I interferon (IFN-I) signature associated with disease activity. We previously identified a link between SARS-CoV-2 infection and the onset or relapse of JDM. Here, we show that newly diagnosed JDM patients display an overexpression of IFIH1 (encoding MDA5 protein) at baseline, coupled with an altered response to dsRNA stimulation at proteomic and transcriptomic levels, indicating abnormal activation of this antiviral sensing pathway. Single-cell transcriptomic and chromatin accessibility profiling of peripheral blood mononuclear cells (PBMCs) further revealed myeloid-specific enrichment of interferon-stimulated genes (ISGs) and preferential disruption of this pathway at disease onset, supporting a dysregulated IFN-I state in this cell type. We identified SARS-CoV-2 RNA in muscle biopsies of two Covid-19 pandemic-onset JDM patients, strongly implicating viral infection as a potential trigger of the dysregulated MDA5 immune response. To extend these observations beyond SARS-CoV-2, we screened two independent retrospective cohorts for antibodies against 27 common childhood infections. In our discovery cohort JDM patients showed significantly increased exposure to 4 RNA viruses in line with our immunological findings. Increased exposure to RSV B was confirmed in an independent replication cohort supporting a robust association with JDM pathophysiology. Together, these findings integrate systemic, single-cell, and tissue-level analyses implicating RNA viral infection and biased antiviral sensing in shaping IFN-I responses at JDM onset, providing mechanistic insight into environmentally triggered pathogenesis. One sentence summaryType I interferon dysregulation at juvenile dermatomyositis onset implicates altered dsRNA sensing and RNA viral exposure as potential disease triggers.

Adult mammals have limited capacity for tissue regeneration, where most injuries resolve through fibrotic scarring rather than functional tissue restoration1-4. Studies in regenerative vertebrate species, including amphibians, teleost fish, reptiles and mammals, have established that the innate immune system plays instructive roles in regeneration5-11, yet the role of adaptive immune cells and how the immune response distinguishes regenerative from non-regenerative injuries, remain poorly understood. The mouse digit tip provides a rare mammalian model of complete multi-tissue regeneration where distal amputation through the terminal phalanx (P3) triggers complete multi-tissue regrowth, whereas a more proximal amputation of the same bone results in fibrotic scarring12-16. Using an intravital multiphoton imaging approach capable of longitudinally tracking bone remodeling and immune cells in live mice17, we find that regulatory T cells (Tregs) are selectively recruited to regenerating but not scarring digit tips. Tregs localize first to sites of osteoclast-mediated bone resorption and persist at the bone surface when an expanding stromal progenitor pool, known as the blastema, initiates digit regrowth. Acute depletion of Tregs impairs bone resorption and subsequent bone regrowth. Mice lacking T and B cells or CD4+ and CD8+ T cells show similar bone remodeling defects, suggesting a dominant role for Tregs within the adaptive immune compartment in promoting mammalian digit tip regeneration. Treg depletion impairs regeneration through an IL-10-independent mechanism, pointing to a non-canonical effector program. Lastly, pharmacological blockade of the chemokine receptor CXCR4 reduces Treg recruitment to the bone compartment, diminishes bone-associated macrophage accumulation, and attenuates bone degradation in regenerative amputations. Together, these findings identify Tregs as essential regulators of bone remodeling during mammalian digit tip regeneration.

Immune dysfunction is a major driver of morbidity and mortality in critical illness syndromes including sepsis. Specifically, CD8+ T cell dysfunction has been linked to organ failure and death. To characterize the immune substructure of circulating CD8+ T cells in critical illness at high dimension, we used single-cell RNA sequencing of peripheral blood CD8+ T cells from 38 critically ill patients and 9 healthy controls. We annotated seven CD8+ T cell clusters, which included a CD8+ effector subset, termed T effector state 2 (TEff-2), that was only present in critically ill patients and associated with more severe respiratory failure and higher mortality. TEff-2 showed effector activation and inflammatory stress conditioning yet had markedly reduced metabolic transcripts without canonical features of exhaustion. Trajectory analyses positioned TEff-2 as a terminal CD8+ T effector cell fate driven in part by DDIT4 and DUSP1, which negatively regulate mTOR and MAPK signaling, respectively. Interestingly, this transcriptional program was indistinguishable by classical protein cytometry methods. These results, including the mortality association, were validated in a larger (n=91) independent external cohort of critically ill patients with sepsis. In summary, TEff-2 represents a latent transcriptional program that delineates a clinically high-risk CD8+ T cell state in critical illness.

Vaccination programs worldwide have effectively reduced the burden of childhood diseases, yet immune responses remain highly heterogeneous among individuals 1,2. While host characteristics such as age and sex are established determinants of vaccine immunogenicity, the timing of vaccination, specifically the calendar season of vaccination, remains largely underexplored 3. Although circadian rhythms are known to regulate daily immune function 4, evidence for long-term circannual patterns has been limited by the difficulty of collecting year-round vaccination data across diverse populations. Here, we show that the season of vaccination systematically shapes the immune response across a broad range of pediatric vaccines. By leveraging data from 96 randomized control trials worldwide, including over 48,000 children vaccinated against 14 pathogens, we demonstrate that immunogenicity after vaccination follows a pronounced latitudinal gradient, typically peaking during colder months in temperate regions and exhibiting distinct variability in the tropics. These findings suggest that the circadian human immune response might extend to a circannual scale, potentially synchronized by environmental cues. Incorporating the season of vaccination into the design of clinical trials and public health campaigns may optimize vaccine performance and enhance seroprotection.

Interferon-{gamma} (IFN{gamma}) signaling is prominent in inflammatory CNS microenvironments across many neurological disorders, but the neuronal peptides presented on HLA class I under these conditions and their functional consequences for CD8+ T cells remain incompletely defined. Here we combine human iPSC-derived human neural aggregates (HNAs), HLA class I immunoprecipitation coupled to LC-MS/MS immunopeptidomics, and microfluidic co-culture assays to map IFN{gamma}-induced neuronal antigen presentation and test antigen-specific cytotoxicity. IFN{gamma} stimulation induced robust HLA class I expression in HNAs and enabled recovery of a canonical 8-12-mer class I ligandome enriched for 9-mers. Neuron-restricted expression of a synapsin-driven polyepitope cassette yielded presentation of defined neoantigen 9-mer peptides on donor HLA class I molecules and, in the presence of IFN{gamma}, elicited activation of autologous antigen-specific CD8+ T cells and consequent antigen-dependent neurite injury. Across four donors, comparative immunopeptidomics identified large IFN{gamma}-unique neural peptide repertoires distinct from matched fibroblasts and revealed a consistent enrichment of predicted high-affinity binders on HLA-B allotypes. Finally, {beta}2-microglobulin deletion ablated peptide recovery, and neuron-restricted {beta}2-microglobulin reconstitution enabled identification of neuron-derived peptides, including peptides derived from neurofilament light (NEFL) that were shared across donors and presented on multiple HLA allotypes. Together, these data provide an integrated platform for neuronal autoantigen discovery and functional validation and support a model in which IFN{gamma}-driven neuronal HLA class I presentation creates an HLA-B-weighted epitope landscape that can be recognized by autoreactive cytotoxic CD8+ T cells.