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Jimmunol.1901059.Full.Pdf Molecular Drivers of Lymphocyte Organization in Vertebrate Mucosal Surfaces: Revisiting the TNF Superfamily Hypothesis This information is current as of October 1, 2021. Ryan D. Heimroth, Elisa Casadei and Irene Salinas J Immunol published online 1 April 2020 http://www.jimmunol.org/content/early/2020/03/31/jimmun ol.1901059 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2020/03/31/jimmunol.190105 Material 9.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 1, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published April 1, 2020, doi:10.4049/jimmunol.1901059 The Journal of Immunology Molecular Drivers of Lymphocyte Organization in Vertebrate Mucosal Surfaces: Revisiting the TNF Superfamily Hypothesis Ryan D. Heimroth, Elisa Casadei, and Irene Salinas The adaptive immune system of all jawed vertebrates relies on the presence of B and T cell lymphocytes that aggregate in specific body sites to form primary and secondary lymphoid structures. Secondary lymphoid organs include organized MALT (O-MALT) such as the tonsils and Peyer patches. O-MALT became progressively organized during vertebrate evolution, and the TNF superfamily of genes has been identified as essential for the formation and maintenance of O-MALT and other secondary and tertiary lymphoid structures in mammals. Yet, the molecular drivers of O-MALT structures found in ectotherms and birds remain essentially unknown. In this study, we provide evidence that TNFSFs, such as lymphotoxins, are likely not a universal mechanism to maintain O-MALT structures in adulthood of teleost fish, sarcopterygian fish, or birds. Although a role for TNFSF2 (TNF-a) Downloaded from cannot be ruled out, transcriptomics suggest that maintenance of O-MALT in nonmammalian vertebrates relies on expression of diverse genes with shared biological functions in neuronal signaling. Importantly, we identify that expression of many genes with olfactory function is a unique feature of mammalian Peyer patches but not the O-MALT of birds or ectotherms. These results provide a new view of O-MALT evolution in vertebrates and indicate that different genes with shared biological functions may have driven the formation of these lymphoid structures by a process of convergent evolution. The Journal of Immunology, 2020, 204: 000–000. http://www.jimmunol.org/ he development and organization of lymphoid tissues was teleosts. SLOs are sites where immune cells interact with each a vital step in the evolution of the vertebrate immune other and immune responses are activated against foreign Ags. T system (1–3). Lymphoid organs can be classified into SLOs, such as the spleen, lymph nodes (LNs), and MALT, are primary and secondary lymphoid organs (SLOs). Primary lym- therefore the birthplace of effective adaptive immune responses. phoid organs are sites of lymphogenesis where lymphocyte pro- SLO formation is genetically programmed, whereas tertiary genitor cells differentiate into B and T lymphocytes. These sites lymphoid structures (TLS) are considered ectopic lymphoid include the bone marrow and the thymus in mammals, the thymus accumulations that appear during adulthood in response to en- by guest on October 1, 2021 and bursa of Fabricius in birds and the thymus and head kidney in vironmental stimuli (4). MALT are immune inductive sites located at mucosal barriers that provide increased protection at areas of high pathogen en- Center for Evolutionary and Theoretical Immunology, University of New Mexico, counter, allowing for efficient Ag trapping and rapid activation of Albuquerque, NM 87131; and Department of Biology, University of New Mexico, the adaptive immune response. MALT includes diffuse MALT Albuquerque, NM 87131 and organized MALT (O-MALT). Diffuse MALT consists of im- Received for publication August 30, 2019. Accepted for publication February 26, 2020. mune cells scattered throughout the epithelium acting as sentinels This work was supported by the National Institutes of Health/National Science Foun- against invading pathogens and is present in all vertebrates from dation Award 1456940 (to I.S.) and National Institutes of Health/Center for Evolu- agnathans to mammals. O-MALT are composed of clusters of tionary and Theoretical Immunology/Centers of Biomedical Research Excellence lymphocytes and can be found in both ectotherms and endo- Grant P20GM103452. therms. Similar to other SLOs, the O-MALT of endotherms is The datasets presented in Supplemental Table II have been submitted to the National Center for Biotechnology Information (https://www.ncbi.nlm.nih.gov/bioproject/ segregated into B and T cell zones, it contains follicular den- PRJNA4868500) under accession number PRJNA4868500. Lungfish TNF sequences dritic cells (FDCs) and the germinal center (GC) reaction allows have been submitted to the National Center for Biotechnology Information’s GenBank for affinity maturation of the adaptive immune response via se- (https://www.ncbi.nlm.nih.gov/genbank/) under accession numbers MK935171– MK935184 (African lungfish TNF super family), MK965520–MK965537 (African lection of high-affinity B cell clones. In ectotherms, however, lungfish TNFR super family), and MN536217– MN536233 (South American TNF little to modest affinity maturation can be detected, and SLOs do superfamily). not have well-defined B and T cell zones (except for the spleen). Address correspondence and reprint requests to Dr. Irene Salinas, Department of The evolutionary origins of O-MALT have long been a subject of Biology, University of New Mexico, 167 Castetter Hall, MSC03-2020, Albuquerque, NM 87131-0001. E-mail address: [email protected] debate among evolutionary immunologists. O-MALT was thought The online version of this article contains supplemental material. to have emerged in anuran amphibians as primitive lymphoid ag- gregates (LAs), but in 2015, primitive O-MALT structures were Abbreviations used in this article: CRD, cysteine-rich domain; CT, cecal tonsil; FDC, follicular dendritic cell; GC, germinal center; HMM, hidden Markov modeling; ILC, found in the gut and nasopharyngeal tissue of African lungfish innate lymphoid cell; ILT, interbranchial lymphoid tissue; LA, lymphoid aggregate; (Sarcopterygii) (5) revealing that O-MALT is an innovation that LN, lymph node; LTi, lymphoid tissue inducer; NCBI, National Center for Biotech- nology Information; O-MALT, organized MALT; OR, olfactory receptor; PP, Peyer predates the emergence of tetrapods. Lungfish LAs are thought patch; RNA-Seq, RNA sequencing; SLO, secondary lymphoid organ; SRA, Sequence to be SLOs because they were present in similar anatomical Read Archive; THD, TNF homology domain; TLO, tertiary lymphoid organ; TLS, locations in all animals examined, and tertiary lymphoid organs tertiary lymphoid structure; TNFN, TNF-new; TNFSF, TNF superfamily. (TLOs) coined as inducible LAs appeared in response to infec- Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 tion (5). Lungfish LAs share features with previously described www.jimmunol.org/cgi/doi/10.4049/jimmunol.1901059 2 MOLECULAR DRIVERS OF VERTEBRATE O-MALT LA in ectotherms because no compartmentalization into B and drivers of lymphocyte organization may be different in different T cell zones or GCs were identified. Importantly, lungfish LAs vertebrate groups. are mostly composed of T cells and, to a lesser extent, B cells. We hypothesize, in this study, that given the diversity of O-MALT Additionally, no evidence for somatic hypermutation was evi- structures and their different degrees of lymphocytic organization dent in lungfish Las, and therefore, the function of these struc- observed in vertebrates, these structures arose by convergent evo- tures remains enigmatic. lution creating lymphocytic aggregations of similar form but po- Although bona fide LAs are not present in teleost fish, a unique tentially different functions. As a consequence, whereas TNFSF O-MALT–like structure known as interbranchial lymphoid tissue may be essential for mammalian O-MALT formation and mainte- (ILT) has been reported in the gill arch of salmonids. The presence nance, alternative molecular drivers may be responsible for these of ILT in Atlantic salmon is intriguing because no other lymphoid processes in other vertebrate groups. To test this hypothesis, we use structures appear to be present in association with other teleost a comparative phylogenetic approach by performing RNA se- mucosal barriers such as the gastrointestinal tract. Similar to quencing (RNA-Seq) of different O-MALT structures obtained from lungfish LAs and in contrast to mammalian SLOs, salmonid ILT mammals, birds, sarcopterygian fish (lungfish), and bony fish, as mostly consists of diverse T cell clusters, shows high expression
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