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Funding Information: We thank the nurses of the Transplantation Unit of Helsinki University Central Hospital, HiLife Flow Cytometry Unit of University of Helsinki, and Tamás Bazsinka for technical support. This study has been funded by Emil Aaltonen Foundation, Finnish Medical Foundation, Foundation for Pediatric Research, Biomedicum Helsinki Foundation, Roche Research grant, the MD PhD program of the University of Helsinki, and the Competitive State Research Financing of Responsibility Area of Helsinki University Hospital (TYH2019307). Publisher Copyright: © 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH. Long-term T-cell memory is dependent on the maintenance of memory T cells in the lymphoid tissues, and at the surface interfaces that provide entry routes for pathogens. However, much of the current information on human T-cell memory is based on analyzing circulating T cells. Here, we have studied the distribution and age-related changes of memory T-cell subsets in samples from blood, mesenteric LNs, spleen, and ileum, obtained from donors ranging in age from 5 days to 67 years of age. Our data show that the main reservoir of polyclonal naive cells is found in the LNs, and the resting memory subsets capable of self-renewal are also prominent there. In contrast, nondividing but functionally active memory subsets dominate the spleen, and especially the ileum. In general, the replacement of naive cells with memory subsets continues throughout our period of observation, with no apparent plateau. In conclusion, the analysis of lymphoid and nonlymphoid tissues reveals a dynamic pattern of changes distinct to each tissue, and with substantial differences between CD4+ and CD8+ compartments.

The Ikaros family transcription factors regulate lymphocyte development. Loss-of-function variants in

Almost all patients with autoimmune polyendocrine syndrome type 1 (APS-1) have neutralizing antibodies against type 1 interferons (IFN), important mediators of antiviral defense. Recently, neutralizing anti-IFN antibodies were shown to be a risk factor of severe COVID-19. Here we show in a cohort of 44 patients with APS-1 that higher titers of neutralizing anti-IFN alpha 4 antibodies are associated with a higher and earlier incidence of VZV reactivation (herpes zoster). The patients also present with uncommonly severe clinical sequelae of herpetic infections. APS-1 patients had decreased humoral immune responses to varicella zoster virus, but cellular responses were comparable to healthy controls. These results suggest that blocking the type I interferon pathway in patients with APS-1 patients leads to a clinically significant immune deficiency, and susceptibility to herpesviruses should be taken into account when treating patients with APS-1.

The IKAROS family transcription factors regulate lymphocyte development. Loss-of-function variants in IKZF1 cause primary immunodeficiency, but IKAROS family members IKZF2 and IKZF3 have not yet been associated with immunodeficiency yet. Here, we describe a pedigree with a heterozygous truncating variant in IKZF2, encoding the translational activator and repressor HELIOS which is highly expressed in regulatory T cells and effector T cells, particularly of the CD8+ T cell lineage. Protein-protein interaction analysis revealed that the variant abolished HELIOS dimerizations as well as binding to members of the Mi-2/NuRD chromatin remodeling complex. Patients carrying the IKZF2 variant presented with a combined immunodeficiency phenotype characterized by recurrent upper respiratory infections, thrush and mucosal ulcers, as well as chronic lymphadenopathy. With extensive immunophenotyping, functional assays, and transcriptional analysis we show that reduced HELIOS expression was associated with chronic T cell activation and increased production of pro-inflammatory cytokines both in effector and regulatory T cells. Lymph node histology from patients indicated dysregulated germinal center reactions. Moreover, affected individuals displayed profoundly reduced circulating MAIT cell numbers. In summary, we show that this novel loss-of-function variant in HELIOS leads to an immunodeficiency with signs of immune overactivation.One sentence summaryTruncating variant of HELIOS causes immunodeficiency with signs of immune overactivation.

Persistence of immune memory in humans is a crucial yet poorly understood aspect of immunology. Here we have studied the effect of Puumala hantavirus infection on unrelated, pre-existing immune memory by studying T cell- and antibody responses against toxoid vaccine antigens of diphtheria, tetanus and pertussis in a cohort of 45 patients. We found that tetanus- and pertussis-specific IgG concentrations elevate during acute Puumala virus infection. Increase in vaccine IgG was associated with proliferation of heterologous T cells. Interestingly, increases in tetanus-specific IgG persisted a year after the infection while pertussis-specific IgG declined rapidly; a difference in IgG kinetics resembling the difference seen after vaccination against tetanus and pertussis. These results suggest that persistence of immune memory is facilitated by heterologous boosting of old memory during memory formation against newly encountered antigens. They also show that different toxoid antigens may be treated differently. Our study gives new insight into how immune memory formation may alter pre-existing immune memory, and also shows that heterologous immunity may have an impact on vaccination outcomes. (C) 2021 Elsevier Ltd. All rights reserved.

High indoleamine 2,3-dioxygenase (IDO) activity is associated with clinically severe acute infection caused by Puumala hantavirus. The immunoregulatory effects of IDO can be mediated either through metabolic control of effector T cells, caused by depletion of the essential amino acid tryptophan, or intercellular signaling and activation of regulatory T cell responses. Here, we have studied 24 patients with acute Puumala hantavirus infection to distinguish between these possibilities. Maximum IDO activity showed a significant positive correlation with FOXP3 expression levels in regulatory T cells, a quantitative surrogate marker for suppressive capability. In contrast, IDO activity did not correlate with the frequency of CD8+ effector cells in cell cycle. The data suggest that in Puumala infection, the mechanism responsible for the suppressive effect of IDO is not metabolic control of effector cells but rather the signaling mediated by tryptophan breakdown products, such as kynurenine.

Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is a monogenic autoimmune disease caused by mutations in the AIRE gene. Although mainly an endocrine disease, a substantial fraction of patients have gastrointestinal manifestations. In this study, we have examined the role of anticommensal responses and their regulation. APECED patients had increased levels of Abs against Saccharomyces cerevisiae (p < 0.0001) and against several species of commensal gut bacteria, but not against species predominantly associated with other locations. The anticommensal Ab levels did not correlate with gastrointestinal autoantibodies, neutralizing anti–IL-17 or –IL-22 Abs, or gastrointestinal symptoms, although scarcity of the available clinical data suggests that further study is required. However, the anti–S. cerevisiae Ab levels showed a significant inverse correlation with FOXP3 expression levels in regulatory T cells (Treg), previously shown to be dysfunctional in APECED. The correlation was strongest in the activated CD45RO+ population (ρ = −0.706; p < 0.01). APECED patients also had decreased numbers of FOXP3+ cells in gut biopsies. These results show that APECED patients develop early and sustained responses to gut microbial Ags in a pattern reminiscent of Crohn’s disease. This abnormal immune recognition of gut commensals is linked to a systemic Treg defect, which is also reflected as a local decrease of gut-associated Treg. To our knowledge, these data are the first to show dysregulated responses to non-self commensal Ags in APECED and indicate that AIRE contributes to the regulation of gut homeostasis, at least indirectly. The data also raise the possibility of persistent microbial stimulation as a contributing factor in the pathogenesis of APECED.

Background Cells of the innate immune system regulate both adaptive immune responses and the maintenance of tolerance, especially in the gut. However, relatively little is known about the effects of complement on lymphocyte homeostasis. Objective This study explored complement C3 deficiency in mice and human subjects for its effect on intestinal tolerance. Methods C3-deficient mice and control C57BL/6 mice were fed ovalbumin (OVA) by means of gavage, and subsequent response to immunization with OVA in Freund's adjuvant was monitored. Serum antibodies against commensal microbes were measured, and the activation status of peripheral blood lymphocytes bearing mucosal homing markers was determined from 2 rare cases of C3-deficient patients. Results We show in C3-deficient mice and human patients that intestinal tolerance fails in the absence of functional complement. In contrast to wild-type control animals, in which oral tolerance was induced, intragastric administration of OVA did not result in a significantly decreased response to subsequent subcutaneous OVA challenge in C3-deficient mice. In the jejunum of C3-deficient mice the cytokine ratio between IL-10 and IFN-γ or IL-17 levels was decreased, indicating a shift in favor of proinflammatory cytokines. In 2 C3-deficient children the frequency of gut-homing T cells expressing activation markers was increased, and the patients had increased serum IgG levels against gut commensal microbes. The data also suggest that the impaired oral tolerance was at least partly caused by the absence of signaling through C3-binding complement regulators in T cells. Conclusions Taken together, our results identify complement as an important and nonredundant regulator of intestinal tolerance.