TYPE Editorial PUBLISHED 07 September 2022 DOI 10.3389/fimmu.2022.993393 Editorial: alternative antigen OPEN ACCESS processing and presentation EDITED AND REVIEWED BY Florent Ginhoux, Singapore Immunology Network in immune disorders (A*STAR), Singapore *CORRESPONDENCE Iñaki Alvarez 1,2*, Luis C. Antón 3* and Eddie A. James 4* Iñaki Alvarez inaki.alvarez@uab.cat 1 Immunology Unit, Department of Cell Biology, Physiology and Immunology, Autonomous Luis C. Antón University of Barcelona, Bellaterra, Spain, 2 Institute of Biotechnology and Biomedicine, lanton@cbm.csic.es Autonomous University of Barcelona, Bellaterra, Spain, 3 Centro de Biologı´a Molecular Severo Eddie A. James Ochoa, CSIC/UAM, C/Nicolás Cabrera, Madrid, Spain, 4 Center for Translational Immunology, ejames@benaroyaresearch.org Benaroya Research Institute, Seattle, WA, United States SPECIALTY SECTION This article was submitted to KEYWORDS Antigen Presenting Cell Biology, a section of the journal antigen (Ag), antigen processing and presentation, MHC class I and class II, alternative Frontiers in Immunology processing, immune disorders RECEIVED 13 July 2022 ACCEPTED 18 July 2022 PUBLISHED 07 September 2022 CITATION Editorial on the Research Topic Alvarez I, Antón LC and James EA (2022) Editorial: alternative antigen Alternative antigen processing and presentation in immune disorders processing and presentation in immune disorders. Front. Immunol. 13:993393. doi: 10.3389/fimmu.2022.993393 COPYRIGHT The key players and processes of the MHC class I and class II pathways were © 2022 Alvarez, Antón and James. This described decades ago and are essential to develop an efficient T cell response. However, is an open-access article distributed they are not confined to canonical pathways only. Indeed, cross-presentation and under the terms of the Creative Commons Attribution License (CC BY). autophagy are non-canonical processes that allow the presentation of peptides by The use, distribution or reproduction MHC-I and MHC-II molecules that originate from proteins located in the endocytic in other forums is permitted, provided the original author(s) and the or endogenous compartments, respectively. In addition, the structural features of the copyright owner(s) are credited and MHC-peptide interaction were described decades ago. Nevertheless, MHC molecules can that the original publication in this bind thousands of different peptides and the complexity of these immunopeptidomes journal is cited, in accordance with accepted academic practice. No use, open the door to the study of “non-typical” peptides. Thus, some of them are post- distribution or reproduction is translationally modified peptides, spliced peptides generated by the proteasome, or permitted which does not comply with these terms. peptides derived from non-canonical open reading frames. In this special Research Topic issue, we wanted to include an array of manuscripts that provides an extensive view of the alternative processing and presentation by MHC molecules and its involvement in immune disorders. A brief synopsis or each (in topical order) is included below. Building on their previously reported work, Mansurkhodzhaev et al. investigate the formation of proteasome-generated spliced zwitter peptides originating from self (human) and non-self (viral) antigens. Although such sequences can be envisioned to induce clonal deletion or other tolerance processes and restrain responses against viruses, their analysis suggests that cis-spliced peptides only marginally impinge upon functional anti-viral CD8+ cytotoxic T cell responses. In his Mini Review Münz highlights basic knowledge about how macroautophagy machinery contributes to antigen processing and presentation, strengthening its noncanonical functions, such as its role in nonconventional phagocytosis and secretion. Therefore, as argued in the manuscript, the multiple tasks played by this Frontiers in Immunology 01 frontiersin.org Alvarez et al. 10.3389/fimmu.2022.993393 machinery makes it a fascinating object of study and, potentially, dendritic cells leading to altered peptide presentation. a powerful target to modulate antigen presentation in Inhibition of membrane movement blocked this effect, leading pathological situations. to suppressed Pd-induced T cell-mediated responses. One of the crucial issues in defining the immunopeptidome The impact of sequence defects or variants on the expression is the discrimination of signal from noise, which becomes critical and function of MHC molecules provides an important means of when peptide abundance is limiting. Nanaware et al. addressed understanding the potential impact of natural polymorphisms this issue aiming at the MHC classs II (MHC-II) and acquired mutations. Zhao et al. explore the functional immunopeptidome in the mouse thymus. They developed a impact of a spontaneous H2-Aa point mutation on MHC II strategy to discard non-binding peptides and to validate bona expression and function. They document an atypical type II bare fide binders, allowing them to identify distinct structural features lymphocyte syndrome mediated through a cascade of erroneous of thymus MHC-II ligands compared to those from spleen, mRNA splicing, deletion of eight bases in the mRNA, and a pointing to differences in antigen processing in these tissues. protein frameshift, all leading to a general loss of expression and Mei et al. presented original research work focused in the significantly impaired CD4+ T cell numbers. need to use computer-based immunoinformatic analysis to In an original research article, Thakur and Luthra- predict T cell targets from different strains of SARS-Cov-2 that Guptasarma elaborate mechanisms through which some HLA- may be used in future vaccine design. The authors put emphasis B27 subtypes are associated with ankylosing spondylitis (AS) in HLA-A*11:01, the most frequent HLA allele in the Chinese and others are not. In their work, they conducted a proteomics- population. They experimentally validated three epitopes from based study to analyze the protein clearance mechanisms in two Spike protein. AS differentially associated alleles (B*27:04, associated, and The role that CD8+ T lymphocytes play in immunosurveillance B*27:09, non-associated). They show that B*27:04 misfolded of cancer cells is highlighted by the evasion mechanisms that they chains are mainly cleared through activation of the unfolded develop that affect MHC-I antigen presentation. This is the topic of protein response (UPR), and autophagy. Instead, the B*27:09 the exhaustive Review by Dhatchinamoorthy et al.., where they misfolded chains are mainly cleared through the endosome- cover different angles from where this issue can be observed: lysosome pathway. mechanisms of downregulation of MHC-I expression, mutations Another topic of great interest is the idea that specific affecting MHC-I itself or essential components of the antigen populations of professional antigen presenting cells can play processing pathway, the impact of these immunoevasion distinct roles in health and disease. Welsh et al. review the often- mechanisms on cancer cell recognition, as well as potential overlooked role of B cell antigen presentation on the strategies to restore MHC-I expression. differentiation and longevity of protective memory CD4 T Carré and Mallone elaborate the physiology and function of cells. Specifically, they highlight the impact of antigen density beta cells and antigen processing and presentation (APP) and the contributions of MHC Class II accessory molecules pathways. Thus, the authors generated some hypotheses on (HLA-DM and HLA-DO) to epitope selection and possible APPs relevant to beta cells, and directed this analysis to T1D impacts on the formation of memory. They propose that low pathogenesis. Finally, the authors raised some gaps regarding the levels of antigen presentation might be to regulate long-term HLA-I immunopeptidomes that need to be filled, as their survival of CD4 memory T cells and to prevent cross-reactivity composition in basal or stress conditions or the differences in to autoantigens. the antigenic peptides presented by beta cells or dendritic cells In their article, Kang et al. investigate the number and during the T cell priming in draining lymph nodes. function of Dendritic cells (DCs) in scrub typhus patients. The contribution of neuroinflammatory processes to the Examining peripheral blood, they observed that plasmacytoid development of Parkinson’s Disease (PD) has been gaining and conventional DCs were numerically deficient and momentum in recent years. Celastrol, a compound that functionally impaired in scrub typhus patients. Alterations in modulates autophagy and mitophagy, has been proposed to the number and surface phenotype of DCs were absent during mitigate PD and other neurodegenerative diseases. The work disease remission, but phenotypic alterations could be of Ng et al. in this issue explores how this natural product may recapitulated through treatment with pro-inflammatory weaken anti-a-synuclein T cell responses through alterations in cytokines, suggesting a direct relationship between these the vesicular trafficking of this antigen in dendritic cells. The alterations and disease severity. authors propose that this altered trafficking may preclude its Kawasaki disease (KD) is a severe illness that primarily efficient antigen processing, thus thwarting a damaging T affects children under the age of five. The condition is cell response. characterized by a vasculitis that, if untreated, can cause Ito et al. explore the effects of palladium metal, a well-known coronary artery aneurism and adult cardiovascular disease. allergen, on the surface dynamics of MHC class I protein. Using Intravenous immunoglobulin (IVIG) is an effective treatment complementary assays, they demonstrated distinct temporal for acute KD, but its therapeutic mechanism of action is not effects elicited by palladium treatment of murine DC2.4 completely understood. Wang et al. suggest in their contribution Frontiers in Immunology 02 frontiersin.org Alvarez et al. 10.3389/fimmu.2022.993393 that IVIG treatment reverts the immature (or tolerant) PID2019-110407RB-I00 from the Ministerio de Ciencia e phenotype of circulating myeloid and plasmacytoid dendritic Innovació n; the Centro de Biologı́a Molecular Severo Ochoa is cells, restoring the numbers of peripheral CD4+ T cells, which funded by institutional grants from Fundació n Ramó n Areces circulate at reduced levels prior to the treatment. and Banco de Santander. EAJ is supported by NIH/NIDDK We would like to dedicate this ResearchTopic to the memory grant no U24 DK104162-08 (Niland) NIAID contract no of two pioneers that the Antigen Presentation field lost in the 75N93019C00068 (Kwok), NIAID grant no 2R01DK081166-11 past few years, Enzo Cerundolo and Nilabh Shastri. Their (Haskins), and an award from the Heidner Foundation. contributions laid the foundations of a knowledge that pervades many concepts used by the papers published in this ResearchTopic. Conflict of interest The authors declare that the research was conducted in the Author contributions absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EAJ, IA, and LCA each wrote individual sections of the editorial, corresponding to the respective articles that they edited. All three authors organized, revised, and edited the Publisher’s note manuscript and agree to its style and content in its final form. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated Funding organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or IA is supported by Grant RTI2018-097414-B-I00 from the claim that may be made by its manufacturer, is not guaranteed Ministerio de Ciencia e Innovació n. LCA is supported by Grant or endorsed by the publisher. Frontiers in Immunology 03 frontiersin.org