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A wide variety of medications can induce adverse immune events and autoimmune responses such as vasculitis. Mechanistically, small molecule drugs known as haptens bind and modify endogenous proteins, triggering such immune reactions. In this issue of the JCI , Xi and colleagues investigated the immunological mechanism of autoimmune vasculitis associated with hydralazine. Notably, hydralazine-based haptenization modified myeloperoxidase (MPO), inducing the enzyme conformational change. The hydralazine-modified MPO induced IgM antibody specific for the modified enzyme, followed by immune complex precipitation, tissue deposition, and complement activation. These findings provide a mechanism by which hydralazine induces a type III hypersensitivity reaction associated with mild to severe vasculitis. The study serves as an example for understanding haptenation and may inform the development of diagnostics for determining susceptibility to drug-induced allergic or autoimmune responses.

In the last few years, advancement in the analysis of the MHC class II (MHC-II) ligandome in several mouse and human haplotypes has increased our understanding of the molecular components that regulate the range and selection of the MHC-II presented peptides, from MHC class II molecule polymorphisms to the recognition of different conformers, functional differences in endosomal processing along the endocytic tract, and the interplay between the MHC class II chaperones DM and DO. The sum of all these variables contributes, qualitatively and quantitatively, to the composition of the MHC II ligandome, altogether ensuring that the immunopeptidome landscape is highly sensitive to any changes in the composition of the intra- and extracellular proteome for a comprehensive survey of the microenvironment for MHC II presentation to CD4 T cells.

Neoantigens generated by somatic nonsynonymous mutations are key targets of tumor-specific T cells, but only a small number of mutations predicted to be immunogenic are presented by MHC molecules on cancer cells. Vaccination studies in mice and patients have shown that the majority of neoepitopes that elicit T cell responses fail to induce significant antitumor activity, for incompletely understood reasons. We report that radiotherapy upregulates the expression of genes containing immunogenic mutations in a poorly immunogenic mouse model of triple-negative breast cancer. Vaccination with neoepitopes encoded by these genes elicited CD8+ and CD4+ T cells that, whereas ineffective in preventing tumor growth, improved the therapeutic efficacy of radiotherapy. Mechanistically, neoantigen-specific CD8+ T cells preferentially killed irradiated tumor cells. Neoantigen-specific CD4+ T cells were required for the therapeutic efficacy of vaccination and acted by producing Th1 cytokines, killing irradiated tumor cells, and promoting epitope spread. Such a cytotoxic activity relied on the ability of radiation to upregulate class II MHC molecules as well as the death receptors FAS/CD95 and DR5 on the surface of tumor cells. These results provide proof-of-principle evidence that radiotherapy works in concert with neoantigen vaccination to improve tumor control.

The MHC- self immunopeptidome of professional antigen presenting cells is a cognate ligand for the TCRs expressed on both conventional and thymic-derived natural regulatory T cells. In regulatory T cells, the TCR signaling associated with MHC-peptide recognition induces antigen specific as well as bystander immunosuppression. On the other hand, TCR activation of conventional T cells is associated with protective immunity. As such the peripheral T cell repertoire is populated by a number of T cells with different phenotypes and different TCRs, which can recognize the same MHC-self-peptide complex, resulting in opposite immunological outcomes. This article summarizes what is known about regulatory and conventional T cell recognition of the MHC-self-immunopeptidome at steady state and in inflammatory conditions associated with increased T and B cell self-reactivity, discussing how changes in the MHC-ligandome including epitope copy number and post-translational modifications can tilt the balance toward the expansion of pro-inflammatory or regulatory T cells.

Until a few years ago, lymphatic vessels and lymphatic endothelial cells (LEC) were viewed as part of a passive conduit for lymph and immune cells to reach lymph nodes (LN). However, recent work has shown that LEC are active immunological players whose interaction with dendritic cells and T cells is of important immunomodulatory relevance. While the immunological interaction between LEC and other immune cells has taken a center stage, molecular analysis of LEC antigen processing and presentation machinery is still lagging. Herein we review the current knowledge of LEC MHC I and MHC II antigen processing and presentation pathways, Including the role of LEC in antigen phagocytosis, classical, and non-classical MHC II presentation, proteasome processing and MHC I presentation, and cross-presentation. The ultimate goal is to provide an overview of the LEC antigen processing and presentation machinery that constitutes the molecular basis for their role in MHC I and MHC II-restricted immune responses.

A wide variety of medications can induce adverse immune events and autoimmune responses such as vasculitis. Mechanistically, small molecule drugs known as haptens bind and modify endogenous proteins, triggering such immune reactions. In this issue of the JCI, Xi and colleagues investigated the immunological mechanism of autoimmune vasculitis associated with hydralazine. Notably, hydralazine-based haptenization modified myeloperoxidase (MPO), inducing the enzyme conformational change. The hydralazine-modified MPO induced IgM antibody specific for the modified enzyme, followed by immune complex precipitation, tissue deposition, and complement activation. These findings provide a mechanism by which hydralazine induces a type III hypersensitivity reaction associated with mild to severe vasculitis. The study serves as an example for understanding haptenation and may inform the development of diagnostics for determining susceptibility to drug-induced allergic or autoimmune responses.

Dynamic contrast-enhanced magnetic resonance imaging (MRI) for tracking glymphatic system transport with paramagnetic contrast such as gadoteric acid (Gd-DOTA) administration into cerebrospinal fluid (CSF) requires pre-contrast data for proper quantification. Here we introduce an alternative approach for glymphatic system quantification in the mouse brain via T1 mapping which also captures drainage of Gd-DOTA to the cervical lymph nodes. The Gd-DOTA injection into CSF was performed on the bench after which the mice underwent T1 mapping using a 3D spoiled gradient echo sequence on a 9.4 T MRI. In Ketamine/Xylazine (KX) anesthetized mice, glymphatic transport and drainage of Gd-DOTA to submandibular and deep cervical lymph nodes was demonstrated as 25–50% T1 reductions in comparison to control mice receiving CSF saline. To further validate the T1 mapping approach we also verified increased glymphatic transport of Gd-DOTA transport in mice anesthetized with KX in comparison with ISO. The novel T1 mapping method allows for quantification of glymphatic transport as well as drainage to the deep and superficial cervical lymph nodes. The ability to measure glymphatic transport and cervical lymph node drainage in the same animal longitudinally is advantageous and time efficient and the coupling between the two systems can be studied and translated to human studies.

Age-related accumulation of ploidy changes is associated with decreased expression of genes controlling chromosome segregation and cohesin functions. To determine the consequences of whole chromosome instability ( W-CIN ) we down-regulated the spindle assembly checkpoint component BUB1 and the mitotic cohesin SMC1A, and used four-color-interphase-FISH coupled with BrdU incorporation and analyses of senescence features to reveal the fate of W-CIN cells. We observed significant correlations between levels of not-diploid cells and senescence-associated features ( SAFs ). W-CIN induced DNA double strand breaks and elevated oxidative stress, but caused low apoptosis. SAFs of W-CIN cells were remarkably similar to those induced by replicative senescence but occurred in only 13 days versus 4 months. Cultures enriched with not-diploid cells acquired a senescence-associated secretory phenotype (SASP) characterized by IL1B, CXCL8, CCL2, TNF, CCL27 and other pro-inflammatory factors including a novel SASP component CLEC11A. These findings suggest that W-CIN triggers premature senescence, presumably to prevent the propagation of cells with an abnormal DNA content. Cells deviating from diploidy have the ability to communicate with their microenvironment by secretion of an array of signaling factors. Our results suggest that aneuploid cells that accumulate during aging in some mammalian tissues potentially contribute to age-related pathologies and inflammation through SASP secretion.

Summary Chaperone-mediated autophagy (CMA), a cellular process that contributes to protein quality control through targeting of a subset of cytosolic proteins to lysosomes for degradation, undergoes a functional decline with age. We have used a mouse model with liver-specific defective CMA to identify changes in proteostasis attributable to reduced CMA activity in this organ with age. We have found that other proteolytic systems compensate for CMA loss in young mice which helps to preserve proteostasis. However, these compensatory responses are not sufficient for protection against proteotoxicity induced by stress (oxidative stress, lipid challenges) or associated with aging. Livers from old mice with CMA blockage exhibit altered protein homeostasis, enhanced susceptibility to oxidative stress and hepatic dysfunction manifested by a diminished ability to metabolize drugs, and a worsening of the metabolic dysregulation identified in young mice. Our study reveals that while the regulatory function of CMA cannot be compensated for in young organisms, its contribution to protein homeostasis can be handled by other proteolytic systems. However, the decline in the compensatory ability identified with age explains the more severe consequences of CMA impairment in older organisms and the contribution of CMA malfunction to the gradual decline in proteostasis and stress resistance observed during aging.

BackgroundNon-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide.1 Despite the promise shown by immune checkpoint inhibitors (ICIs) in enhancing survival and tumor control for a subset of patients, a significant portion remains non-responsive, which may be attributed to a deficiency in CD8 T-cell tumor infiltration. The presence of pre-existing tumor-reactive T-cell infiltration is, in fact, a crucial determinant of ICI efficacy. Interestingly, despite NSCLC tumors with KRAS and TP53 mutations showcasing pronounced T-cell infiltration, ICI response rates stand at about 35%, pointing to varied tumor-reactive T-cell functionalities. This inconsistency suggests that the functional states of tumor-reactive T-cells vary considerably among patients. Central to these challenges is the immunosuppressive milieu of the lung tumor microenvironment that can be attributed to impaired peptide presentation in the tumor-draining lymph nodes together with a persistent IFN-γ activation signature.2–6 Methods and ResultsIn this study, we spotlight the role of transcription factor EB (TFEB), crucial for autophagy and MHC-II peptide presentation.7 Specifically, TFEB exhibited consistent overexpression in lung tissue-draining mediastinal lymph nodes, contrasting other lymphatic regions. Notably, overexpressing TFEB in CD11c+ dendritic cells augmented tumor-specific CD4 T-cell responses, yet reduced CD8 T-cell activities, suggesting a potential shift towards a tolerogenic immune environment in NSCLC.ConclusionsConclusively, our insights into TFEB’s function in NSCLC highlight the complex relationship between tissue-specific elements and tumor immunogenicity, offering avenues for refining immunotherapeutic strategies.ReferencesSiegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023; 73 (1):17–48. DOI: 10.3322/caac.21763.Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature 2018; 553 (7689):446–454. DOI: 10.1038/nature25183.Network CGAR. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489 (7417):519–525. DOI: 10.1038/nature11404.Garon EB, Hellmann MD, Rizvi NA, Carcereny E, Leighl NB, Ahn MJ, Eder JP, Balmanoukian AS, Aggarwal C, Horn L, et al. Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. J Clin Oncol 2019; 37 (28):2518–2527. DOI: 10.1200/JCO.19.00934.Horton BL, Morgan DM, Momin N, Zagorulya M, Torres-Mejia E, Bhandarkar V, Wittrup KD, Love JC, Spranger S. Lack of CD8+ T cell effector differentiation during priming mediates checkpoint blockade resistance in non-small cell lung cancer. Sci Immunol 2021; 6 (64):eabi8800. DOI: 10.1126/sciimmunol.abi8800.Zagorulya M, Yim L, Morgan DM, Edwards A, Torres-Mejia E, Momin N, McCreery CV, Zamora IL, Horton BL, Fox JG, et al. Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer. Immunity 2023; 56 (2):386–405.e310. DOI: 10.1016/j.immuni.2023.01.010.Samie M, Cresswell P. The transcription factor TFEB acts as a molecular switch that regulates exogenous antigen-presentation pathways. Nat Immunol 2015; 16 (7):729–736. DOI: 10.1038/ni.3196.Ethics ApprovalThe mouse protocol has been approved by Weill Cornell Medicine committee: 2020-0017