MicroRNAs (miRNAs) typically regulate gene expression by promoting mRNA degradation, but select miRNAs, such as miR-466l-3p (miR-466), can instead stabilize transcripts in coordination with RNA-binding proteins (RBPs) like HuR. We identify conserved AU-rich elements (cAREs) within the 3'-UTRs of IL-17A, GM-CSF, and IL-23A as critical cis-regulatory binding site where miR-466 facilitates HuR recruitment to promote mRNA stability. Using site-directed mutagenesis, RNA pulldown, and MS2-TRAP assays to capture miRNA-mRNA complexes, we demonstrate that HuR binding depends on prior engagement by miR-466. Disrupting this interaction with rationally designed Target Site Blockers (TSBs) destabilizes target mRNAs and suppresses cytokine expression in vitro and in vivo. TSBs directed against IL-17A, GM-CSF, and IL-23A selectively blocked miR-466 binding, reduced transcript stability, and lowered cytokine production without affecting unrelated mRNAs. In murine models of LPS-induced inflammation, psoriasis, and autoimmunity, TSBs exhibited therapeutic efficacy and cytokine specificity, outperforming monoclonal antibodies in some settings. Phosphorothioate-modified TSBs enabled systemic delivery and retained activity in human T cells, underscoring translational potential. Similar to antisense oligonucleotides, TSBs trigger RNase H1-mediated degradation while also blocking miRNA-mRNA interactions. These findings establish miR--66-HuR cooperation as a therapeutically targetable axis through TSBs without affecting global miRNA function.

Lymphoid organ development occurs in ontogeny in the absence of antigenic stimulation; inflammation occurs after some immunological insult. These subjects had originally been considered as separate fields of research. Inflammation is due to inflammatory mediators such as lymphotoxin (LT) and its close relative, tumor necrosis factor (TNF). The two fields converged with the realization that LT is also crucial for secondary lymphoid organ (SLO) development and that it induces chronic lymphoid infiltrates, called tertiary lymphoid organs (TLOs) or tertiary lymphoid structures (TLSs) that are remarkably like SLOs. TLSs, which were initially described in mice transgenic for the rat insulin promoter driving LT (RIPLT mice), occur in chronic inflammation in autoimmune diseases, atherosclerosis, graft rejection, microbial infection, aging, and cancer. The thesis presented here is that understanding SLO development, structure, and function is key to understanding TLSs. Key discoveries are presented which include the observations that LT's two forms, LTα3 and LTα1β2, signal through different receptors that induce both SLOs and TLSs. Similarities and differences between TLSs and SLOs are presented. Prospects for their inhibition in autoimmune diseases where they are detrimental, and induction in cancer, where they are beneficial, are presented. Challenges and future directions are discussed.

Tertiary lymphoid structures (TLS) are accumulations of lymphoid cells that arise in ectopic sites through the process of lymphoid neogenesis in chronic inflammation in autoimmunity, microbial infections, organ rejection, aging, and cancer. Their cellular composition and function and regulation via members of the lymphotoxin (LT)/tumor necrosis factor (TNF) family resemble that of secondary lymphoid organs (SLOs). Tumor-associated (TA)-TLS can be associated with favorable clinical outcomes. Immunotherapy in the form of immune checkpoint inhibitors (ICI) has contributed to tremendous advances in cancer therapy. However, ICI are effective in only some tumors, can give rise to resistance, and can precipitate immune-related adverse events (irAEs), many of which appear to have hallmarks of autoimmunity and can resemble TLS. TA-TLS correlate with a positive response to immunotherapy, but they can also be associated with susceptibility to irAEs, suggesting that TA-TLS in combination with ICI could lead to uncontrolled autoimmunity. The tumor environment can be manipulated to ensure that, not only the number of TLS, but also their cellular composition and appropriate function allow for judicious combinations of TLS and immunotherapy that can synergize and contribute to better outcomes with a minimum of destructive irAEs. Strategies include directed delivery of lymphoneogenic cytokines and chemokines or vascular growth factors directly, via transgenes or via adenovirus vectors.

High endothelial venules (HEVs), high walled cuboidal blood vessels, through their expression of adhesion molecules and chemokines, allow the entrance of lymphoid cells into primary, secondary, and tertiary lymphoid structures (aka tertiary lymphoid organs). HEV heterogeneity exists between various lymphoid organs in their expression of peripheral node addressin (PNAd) and mucosal vascular addressin adhesion molecule 1(MAdCAM-1). Transcriptomic analyses reveal extensive heterogeneity, plasticity, and regulation of HEV gene expression in ontogeny, acute inflammation, and chronic inflammation within and between lymphoid organs. Rules regulating HEV development are flexible in inflammation. HEVs in tumor tertiary lymphoid structures are diagnostic of favorable clinical outcome and response to Immunotherapy, including immune check point blockade. Immunotherapy induces HEVs and provides an entrance for naïve, central memory, and effector cells and a niche for stem like precursor cells. Understanding HEV regulation will permit their exploitation as routes for drug delivery to autoimmune lesions, rejecting organs, and tumors.

Tertiary lymphoid organs (TLOs), also known as tertiary or ectopic lymphoid structures or tissues, are accumulations of lymphoid cells in sites other than canonical lymphoid organs, that arise through lymphoid neogenesis during chronic inflammation in autoimmunity, microbial infection, cancer, aging, and transplantation, the focus of this review. Lymph nodes and TLOs are compared regarding their cellular composition, organization, vascular components, and migratory signal regulation. These characteristics of posttransplant TLOs (PT-TLOs) are described with individual examples in a wide range of organs including heart, kidney, trachea, lung, artery, skin, leg, hand, and face, in many species including human, mouse, rat, and monkey. The requirements for induction and maintenance of TLOs include sustained exposure to autoantigens, alloantigens, tumor antigens, ischemic reperfusion, nephrotoxic agents, and aging. Several staging schemes have been put forth regarding their function in organ rejection. PT-TLOs most often are associated with organ rejection, but in some cases contribute to tolerance. The role of PT-TLOs in cancer is considered in the case of immunosuppression. Furthermore, TLOs can be associated with development of lymphomas. Challenges for PT-TLO research are considered regarding staging, imaging, and opportunities for their therapeutic manipulation to inhibit rejection and encourage tolerance.

Treating macaques with an anti-α4β7 antibody under the umbrella of combination antiretroviral therapy (cART) during early SIV infection can lead to viral remission, with viral loads maintained at < 50 SIV RNA copies/ml after removal of all treatment in a subset of animals. Depletion of CD8+ lymphocytes in controllers resulted in transient recrudescence of viremia, suggesting that the combination of cART and anti-α4β7 antibody treatment led to a state where ongoing immune responses kept the virus undetectable in the absence of treatment. A previous mathematical model of HIV infection and cART incorporates immune effector cell responses and exhibits the property of two different viral load set-points. While the lower set-point could correspond to the attainment of long-term viral remission, attaining the higher set-point may be the result of viral rebound. Here we expand that model to include possible mechanisms of action of an anti-α4β7 antibody operating in these treated animals. We show that the model can fit the longitudinal viral load data from both IgG control and anti-α4β7 antibody treated macaques, suggesting explanations for the viral control associated with cART and an anti-α4β7 antibody treatment. This effective perturbation to the virus-host interaction can also explain observations in other nonhuman primate experiments in which cART and immunotherapy have led to post-treatment control or resetting of the viral load set-point. Interestingly, because the viral kinetics in the various treated animals differed-some animals exhibited large fluctuations in viral load after cART cessation-the model suggests that anti-α4β7 treatment could act by different primary mechanisms in different animals and still lead to post-treatment viral control. This outcome is nonetheless in accordance with a model with two stable viral load set-points, in which therapy can perturb the system from one set-point to a lower one through different biological mechanisms.

BackgroundAmong the most consequential unknowns of the devastating COVID-19 pandemic are the durability of immunity and time to likely reinfection. There are limited direct data on SARS-CoV-2 long-term immune responses and reinfection. The aim of this study is to use data on the durability of immunity among evolutionarily close coronavirus relatives of SARS-CoV-2 to estimate times to reinfection by a comparative evolutionary analysis of related viruses SARS-CoV, MERS-CoV, human coronavirus (HCoV)-229E, HCoV-OC43, and HCoV-NL63.MethodsWe conducted phylogenetic analyses of the S, M, and ORF1b genes to reconstruct a maximum-likelihood molecular phylogeny of human-infecting coronaviruses. This phylogeny enabled comparative analyses of peak-normalised nucleocapsid protein, spike protein, and whole-virus lysate IgG antibody optical density levels, in conjunction with reinfection data on endemic human-infecting coronaviruses. We performed ancestral and descendent states analyses to estimate the expected declines in antibody levels over time, the probabilities of reinfection based on antibody level, and the anticipated times to reinfection after recovery under conditions of endemic transmission for SARS-CoV-2, as well as the other human-infecting coronaviruses.FindingsWe obtained antibody optical density data for six human-infecting coronaviruses, extending from 128 days to 28 years after infection between 1984 and 2020. These data provided a means to estimate profiles of the typical antibody decline and probabilities of reinfection over time under endemic conditions. Reinfection by SARS-CoV-2 under endemic conditions would likely occur between 3 months and 5·1 years after peak antibody response, with a median of 16 months. This protection is less than half the duration revealed for the endemic coronaviruses circulating among humans (5–95% quantiles 15 months to 10 years for HCoV-OC43, 31 months to 12 years for HCoV-NL63, and 16 months to 12 years for HCoV-229E). For SARS-CoV, the 5–95% quantiles were 4 months to 6 years, whereas the 95% quantiles for MERS-CoV were inconsistent by dataset.InterpretationThe timeframe for reinfection is fundamental to numerous aspects of public health decision making. As the COVID-19 pandemic continues, reinfection is likely to become increasingly common. Maintaining public health measures that curb transmission—including among individuals who were previously infected with SARS-CoV-2—coupled with persistent efforts to accelerate vaccination worldwide is critical to the prevention of COVID-19 morbidity and mortality.FundingUS National Science Foundation.

Tertiary lymphoid organs (TLOs), also known as inducible lymphoid organs, tertiary lymphoid structures, tertiary lymphoid tissues, or ectopic lymphoid organs are accumulations of cells in chronic inflammation that have been observed in most tissues in autoimmunity, infection, and cancer in mouse and man. They share many properties with secondary lymphoid organs (SLOs), particularly lymph nodes, with regard to cellular composition, function, and regulation. TLOs include T and B cells, dendritic cells, follicular dendritic cells, and many other stromal cells, and high endothelial venules (HEVs) and lymphatic vessels. They serve as sites of antigen presentation and tolerance induction; they are harmful in autoimmunity and can be both harmful and beneficial in cancer. SLO induction in ontogeny is mediated by interactions of several cell types, including CD4+ CD3- lymphoid tissue inducer (LTi) RORγt+ cells that express LTαβ and interact with mesenchymal lymphoid tissue organizer (LTo) FAP+ cells in the presence of lymphatic and blood vessels. A variety of inducer cells initiate TLOs, including bona fide LTi cells, T cells, B cells, and NK cells. The mesenchymal organizer cells are less well characterized but can include FAP+ cells. Current challenges include identification of methods to inhibit TLOs in autoimmunity without affecting SLOs, and enhancement of TLOs for defense against tumors.

To investigate the role of lymphotoxin (LT) in Sjögren's syndrome (SS) and in mucosal associated lymphoid tissue (MALT)‐lymphoma, we made transgenic mice (Amy1‐LTαβ) that targeted LTα and LTβ to the salivary and lacrimal glands. Amy1‐LTαβ mice developed atrophic salivary and lacrimal glands that contained tertiary lymphoid organs (TLOs) and had reduced tear production. Amy1‐LTαβ mice developed cervical lymphadenopathy but not MALT‐lymphoma. TLO formation in the salivary and lacrimal glands of Amy1‐LTαβ was not sufficient to induce autoimmunity as measured by autoantibody titres.

During aging, visceral adiposity is often associated with alterations in adipose tissue (AT) leukocytes, inflammation, and metabolic dysfunction. However, the contribution of AT B cells in immunometabolism during aging is unexplored. Here, we show that aging is associated with an expansion of a unique population of resident non-senescent aged adipose B cells (AABs) found in fat-associated lymphoid clusters (FALCs). AABs are transcriptionally distinct from splenic age-associated B cells (ABCs) and show greater expansion in female mice. Functionally, whole-body B cell depletion restores proper lipolysis and core body temperature maintenance during cold stress. Mechanistically, the age-induced FALC formation, AAB, and splenic ABC expansion is dependent on the Nlrp3 inflammasome. Furthermore, AABs express IL-1R, and inhibition of IL-1 signaling reduces their proliferation and increases lipolysis in aging. These data reveal that inhibiting Nlrp3-dependent B cell accumulation can be targeted to reverse metabolic impairment in aging AT.

went beyond describing prevalence/incidence of disease for epidemiology component Abstract did not go beyond describing prevalence/ incidence of disease Abstract went beyond describing general diagnostics or vaccine efficacy Abstract did not go beyond describing general diagnostics or vaccine efficacywent beyond describing general diagnostics or vaccine efficacy Abstract did not go beyond describing general diagnostics or vaccine efficacy Paper was published after 1980 Paper was published before 1980 and/or contained outdated information Complete record Incomplete record (i.e. figure or table, not an article) Appendix