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Due to direct contact with aquatic environment, mucosal surfaces of teleost fish are continuously exposed to a vast number of pathogens and also inhabited by high densities of commensal microbiota. The B cells and immunoglobulins within the teleost mucosa-associated lymphoid tissues (MALTs) play key roles in local mucosal adaptive immune responses. So far, three Ig isotypes (i.e., IgM, IgD, and IgT/Z) have been identified from the genomic sequences of different teleost fish species. Moreover, teleost Igs have been reported to elicit mammalian-like mucosal immune response in six MALTs: gut-associated lymphoid tissue (GALT), skin-associated lymphoid tissue (SALT), gill-associated lymphoid tissue (GIALT), nasal-associated lymphoid tissue (NALT), and the recently discovered buccal and pharyngeal MALTs. Critically, analogous to mammalian IgA, teleost IgT represents the most ancient Ab class specialized in mucosal immunity and plays indispensable roles in the clearance of mucosal pathogens and the maintenance of microbiota homeostasis. Given these, this review summarizes the current findings on teleost Igs, MALTs, and their immune responses to pathogenic infection, vaccination and commensal microbiota, with the purpose of facilitating future evaluation and rational design of fish vaccines.

Dietary vitamin A during pregnancy is required for the formation of secondary lymphoid organs of the developing embryo and affects the offspring’s immune competence in adulthood. Vitamin A needed for offspring immunity This comparison of pregnant mice on diets completely lacking vitamin A, and with low and high vitamin A content, reveals a role for maternal vitamin A metabolites — notably retinoic acid — in establishing innate immunity in the developing fetus. The vitamin is required for the formation of secondary lymphoid organs during embryonic development and affects the offspring's immune competence during adulthood. The impact of nutritional status during fetal life on the overall health of adults has been recognized 1 ; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed 2 , 3 . Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells 2 , 3 , 4 , 5 . Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero , which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.

HIV-1-infected cells persist indefinitely despite the use of combination antiretroviral therapy (ART), and novel therapeutic strategies to target and purge residual infected cells in individuals on ART are urgently needed. Here, we demonstrate that CD4+ T cell-associated HIV-1 RNA is often highly enriched in cells expressing CD30, and that cells expressing this marker considerably contribute to the total pool of transcriptionally active CD4+ lymphocytes in individuals on suppressive ART. Using in situ RNA hybridization studies, we show co-localization of CD30 with HIV-1 transcriptional activity in gut-associated lymphoid tissues. We also demonstrate that ex vivo treatment with brentuximab vedotin, an antibody-drug conjugate (ADC) that targets CD30, significantly reduces the total amount of HIV-1 DNA in peripheral blood mononuclear cells obtained from infected, ART-suppressed individuals. Finally, we observed that an HIV-1-infected individual, who received repeated brentuximab vedotin infusions for lymphoma, had no detectable virus in peripheral blood mononuclear cells. Overall, CD30 may be a marker of residual, transcriptionally active HIV-1 infected cells in the setting of suppressive ART. Given that CD30 is only expressed on a small number of total mononuclear cells, it is a potential therapeutic target of persistent HIV-1 infection.

Tissue-specific autoimmunity occurs when selected antigens presented by susceptible alleles of the major histocompatibility complex are recognized by T cells. However, the reason why certain specific self-antigens dominate the response and are indispensable for triggering autoreactivity is unclear. Spontaneous presentation of insulin is essential for initiating autoimmune type 1 diabetes in non-obese diabetic mice 1 , 2 . A major set of pathogenic CD4 T cells specifically recognizes the 12–20 segment of the insulin B-chain (B:12–20), an epitope that is generated from direct presentation of insulin peptides by antigen-presenting cells 3 , 4 . These T cells do not respond to antigen-presenting cells that have taken up insulin that, after processing, leads to presentation of a different segment representing a one-residue shift, B:13–21 4 . CD4 T cells that recognize B:12–20 escape negative selection in the thymus and cause diabetes, whereas those that recognize B:13–21 have only a minor role in autoimmunity 3 – 5 . Although presentation of B:12–20 is evident in the islets 3 , 6 , insulin-specific germinal centres can be formed in various lymphoid tissues, suggesting that insulin presentation is widespread 7 , 8 . Here we use live imaging to document the distribution of insulin recognition by CD4 T cells throughout various lymph nodes. Furthermore, we identify catabolized insulin peptide fragments containing defined pathogenic epitopes in β-cell granules from mice and humans. Upon glucose challenge, these fragments are released into the circulation and are recognized by CD4 T cells, leading to an activation state that results in transcriptional reprogramming and enhanced diabetogenicity. Therefore, a tissue such as pancreatic islets, by releasing catabolized products, imposes a constant threat to self-tolerance. These findings reveal a self-recognition pathway underlying a primary autoantigen and provide a foundation for assessing antigenic targets that precipitate pathogenic outcomes by systemically sensitizing lymphoid tissues. A sensitive T cell tracking assay reveals immunogenic activity of specific catabolized peptide fragments of insulin and their effects on T cell activity in lymph nodes, highlighting communication between pancreatic islets and lymphoid tissue.

Lymphoid tissue inducer (LTi) cells are critical for inducing the differentiation of most secondary lymphoid organs (SLOs) in mice. In humans, JAK3 and γc deficiencies result in severe combined immunodeficiency (SCIDs) characterized by an absence of T cells, natural killer cells, innate lymphoid cells (ILCs), and presumably LTi cells. Some of these patients have undergone allogeneic stem cell transplantation (HSCT) in the absence of myeloablation, which leads to donor T cell engraftment, while other leukocyte subsets are of host origin. By using MRI to look for SLOs in nine of these patients 16 to 44 y after HSCT, we discovered that SLOs were exclusively found in the three areas of the abdomen that drain the intestinal tract. A postmortem examination of a child with γc-SCID who had died 3.5 mo after HSCT showed corticomedullary differentiation in the thymus, T cell zones in the spleen, and the appendix, but in neither lymph nodes nor Peyer patches. Tertiary lymphoid organs were observed in the lung. No RAR-related orphan receptor-positive LTi cells could be detected in the existing lymphoid structures. These results suggest that while LTi cells are required for the genesis of most SLOs in humans, SLO in the appendix and in gut-draining areas, as well as tertiary lymphoid organs, can be generated likely by LTi cell-independent mechanisms.

Key Points The earliest event in lymph node development is the initial clustering of lymphoid-tissue inducer (LTi) cells at the location where lymph nodes will form. Attraction to this location is regulated by expression of CXC-chemokine ligand 13 (CXCL13). Recent studies suggest that this might be induced by retinoic acid produced by nearby nerve fibres. Both lymph node and Peyer's patch development require the induction of lymphotoxin-α 1 β 2 (LTα 1 β 2 ) expression by LTi cells, which enables them to interact with lymphotoxin-β receptor (LTβR) expressed by stromal organizer cells. Signalling through LTβR on stromal organizer cells leads to the expression of chemokines, adhesion molecules and cytokines that are required for the attraction, retention and survival of haematopoietic cells in the developing lymphoid tissue. The formation of mucosal-associated lymphoid tissues differs from the formation of lymph nodes and Peyer's patches. For nasopharynx-associated lymphoid tissues, the homeostatic chemokines are not needed, whereas for tear duct-associated lymphoid tissue LTi cells are not necessary, and both can form independently of LTβR signalling. During chronic inflammation tertiary lymphoid structures form directly at the site of inflammation. When they develop in response to a viral infection they contribute to the production of antiviral immunity and can be viewed as beneficial for the host. By contrast, those that develop in autoimmune diseases may support the activation of autoreactive cells. This Review focuses on the earliest steps in the formation of lymphoid tissues during embryogenesis, describing the cellular and molecular requirements. The authors compare this with the development of lymphoid structures in mucosal tissues after birth and of tertiary lymphoid organs at sites of chronic inflammation. Secondary lymphoid organs are important locations for the initiation of adaptive immune responses. They develop before birth, and their formation requires interaction between lymphotoxin-α 1 β 2 -expressing lymphoid-tissue inducer cells and lymphotoxin-β receptor-expressing stromal organizer cells. Here, we discuss new insights into the earliest phases of peripheral lymph node and Peyer's patch formation that occur before lymphotoxin-β receptor signalling and suggest a role for the developing nervous system. In addition, we discuss the differing requirements for the postnatal formation of mucosa-associated lymphoid tissues and tertiary lymphoid structures that develop at sites of chronic inflammation.

Paratuberculosis (PTB) is a chronic granulomatous enteritis caused by Mycobacterium avium subsp. paratuberculosis (Map). Vaccination is one of the most cost-effective tools for PTB control, although alternative treatments like the probiotic Dietzia have been explored with promising results. Using a rabbit model, we investigated the association of immunological and microbiota profiles in Gut Associated Lymphoid Tissue (GALT) with the effects in protection induced by the administration of Dietzia spp., the commercial vaccine (Silirum ® ) and the combination of both. The treatment with the probiotic diminished inflammation, but failed to control Map burden, suggesting a detrimental effect. Rabbits treated with the probiotic presented the highest rates of tissue lesion extension, although the immunological profile was not suggestive of an inflammatory state. Map load in both vaccinated groups was similar indicating that both treatments are equally effective in eliminating the infection, suggesting the role of vaccination in eliminating the infection prevails over the immunomodulatory effects of the probiotic. There were slight variations in the presence of some taxonomic groups depending on the treatment, highlighting the complexity of microbial interactions and the need to optimise treatment combinations in the context of each disease and animal species.

Gut microbiota has emerged as an important environmental factor in the pathobiology of multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). Both genetic and environmental factors have been shown to play an important role in MS. Among genetic factors, the human leukocyte antigen (HLA) class II allele such as HLA-DR2, DR3, DR4, DQ6, and DQ8 show the association with the MS. We have previously used transgenic mice expressing MS susceptible HLA class II allele such as HLA-DR2, DR3, DQ6, and DQ8 to validate significance of HLA alleles in MS. Although environmental factors contribute to 2/3 of MS risk, less is known about them. Gut microbiota is emerging as an imporatnt environmental factor in MS pathogenesis. We and others have shown that MS patients have distinct gut microbiota compared to healthy control (HC) with a lower abundance of Prevotella . Additionally, the abundance of Prevotella increased in patients receiving disease-modifying therapies (DMTs) such as Copaxone and/or Interferon-beta (IFNβ). We have previously identified a specific strain of Prevotella ( Prevotella histicola ), which can suppress experimental autoimmune encephalomyelitis (EAE) disease in HLA-DR3.DQ8 transgenic mice. Since Interferon-β-1b [IFNβ (Betaseron)] is a major DMTs used in MS patients, we hypothesized that treatment with the combination of P. histicola and IFNβ would have an additive effect on the disease suppression. We observed that treatment with P. histicola suppressed disease as effectively as IFNβ. Surprisingly, the combination of P. histicola and IFNβ was not more effective than either treatment alone. P. histicola alone or in combination with IFNβ increased the frequency and number of CD4 + FoxP3 + regulatory T cells in the gut-associated lymphoid tissue (GALT). Treatment with P. histicola alone, IFNβ alone, and in the combination decreased frequency of pro-inflammatory IFN-γ and IL17-producing CD4 + T cells in the CNS. Additionally, P. histicola alone or IFNβ alone or the combination treatments decreased CNS pathology, characterized by reduced microglia and astrocytic activation. In conclusion, our study indicates that the human gut commensal P. histicola can suppress disease as effectively as commonly used MS drug IFNβ and may provide an alternative treatment option for MS patients.

IgA is necessary for maintaining gut homeostasis, and its production depends on microbial sampling by the gut-associated lymphoid tissue (GALT). Takayanagi and colleagues identify a novel population of mesenchymal cells in the GALT that control M cell differentiation and function of gut epithelium. Immunoglobulin A (IgA) maintains a symbiotic equilibrium with intestinal microbes. IgA induction in the gut-associated lymphoid tissues (GALTs) is dependent on microbial sampling and cellular interaction in the subepithelial dome (SED). However it is unclear how IgA induction is predominantly initiated in the SED. Here we show that previously unrecognized mesenchymal cells in the SED of GALTs regulate bacteria-specific IgA production and diversify the gut microbiota. Mesenchymal cells expressing the cytokine RANKL directly interact with the gut epithelium to control CCL20 expression and microfold (M) cell differentiation. The deletion of mesenchymal RANKL impairs M cell–dependent antigen sampling and B cell–dendritic cell interaction in the SED, which results in a reduction in IgA production and a decrease in microbial diversity. Thus, the subepithelial mesenchymal cells that serve as M cell inducers have a fundamental role in the maintenance of intestinal immune homeostasis.

Tertiary lymphoid structures (TLSs) are defined as lymphoid aggregates formed in non-hematopoietic organs under pathological conditions. Similar to secondary lymphoid organs (SLOs), the formation of TLSs relies on the interaction between lymphoid tissue inducer (LTi) cells and lymphoid tissue organizer (LTo) cells, involving multiple cytokines. Heterogeneity is a distinguishing feature of TLSs, which may lead to differences in their functions. Growing evidence suggests that TLSs are associated with various diseases, such as cancers, autoimmune diseases, transplant rejection, chronic inflammation, infection, and even ageing. However, the detailed mechanisms behind these clinical associations are not yet fully understood. The mechanisms by which TLS maturation and localization affect immune function are also unclear. Therefore, it is necessary to enhance the understanding of TLS development and function at the cellular and molecular level, which may allow us to utilize them to improve the immune microenvironment. In this review, we delve into the composition, formation mechanism, associations with diseases, and potential therapeutic applications of TLSs. Furthermore, we discuss the therapeutic implications of TLSs, such as their role as markers of therapeutic response and prognosis. Finally, we summarize various methods for detecting and targeting TLSs. Overall, we provide a comprehensive understanding of TLSs and aim to develop more effective therapeutic strategies.