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Toll‐like receptors (TLR) control the activation of dendritic cells that prime CD4+ T cells in draining lymph nodes, where these T cells then undergo massive clonal expansion. The mechanisms controlling this clonal T cell expansion are poorly defined. Using the CD4+ T cell‐mediated disease experimental autoimmune encephalomyelitis (EAE), we show here that this process is markedly suppressed when TLR9 signaling is increased, without noticeably affecting the transcriptome of primed T cells, indicating a purely quantitative effect on CD4+ T cell expansion. Addressing the underpinning mechanisms revealed that CD4+ T cell expansion was preceded and depended on the accumulation of neutrophils in lymph nodes a few days after immunization. Underlying the importance of this immune regulation pathway, blocking neutrophil accumulation in lymph nodes by treating mice with a TLR9 agonist inhibited EAE progression in mice with defects in regulatory T cells or regulatory B cells, which otherwise developed a severe chronic disease. Collectively, this study demonstrates the key role of neutrophils in the quantitative regulation of antigen‐specific CD4+ T cell expansion in lymph nodes, and the counter‐regulatory role of TLR signaling in this process. [ABSTRACT FROM AUTHOR]

Pulmonary mucosal immune response is critical for preventing opportunistic Aspergillus fumigatus infections. Although fungus‐specific CD4+ T cells in blood are described to reflect the actual host–pathogen interaction status, little is known about Aspergillus‐specific pulmonary T‐cell responses. Here, we exploit the domestic pig as human‐relevant large animal model and introduce antigen‐specific T‐cell enrichment in pigs to address Aspergillus‐specific T cells in the lung compared to peripheral blood. In healthy, environmentally Aspergillus‐exposed pigs, the fungus‐specific T cells are detectable in blood in similar frequencies as observed in healthy humans and exhibit a Th1 phenotype. Exposing pigs to 106 cfu/m3 conidia induces a long‐lasting accumulation of Aspergillus‐specific Th1 cells locally in the lung and also systemically. Temporary immunosuppression during Aspergillus‐exposure showed a drastic reduction in the lung‐infiltrating antifungal T‐cell responses more than 2 weeks after abrogation of the suppressive treatment. This was reflected in blood, but to a much lesser extent. In conclusion, by using the human‐relevant large animal model the pig, this study highlights that the blood clearly reflects the mucosal fungal‐specific T‐cell reactivity in environmentally exposed as well as experimentally exposed healthy pigs. But, immunosuppression significantly impacts the mucosal site in contrast to the initial systemic immune response. [ABSTRACT FROM AUTHOR]

Abstract: Conflicting evidence has been provided as to whether induction of intestinal inflammation by adoptive transfer of naïve T cells into Rag−/− mice requires expression of the transcription factor T‑bet by the T cells. Here, we formally show that the intestinal microbiota composition of the Rag−/− recipient determines whether or not T‐bet‐deficient Th cells can induce colitis and we have resolved the differences of the two microbiomes, permissive or non‐permissive to T‐bet‐independent colitis. Our data highlight the dominance of the microbiota over particular T cell differentiation programs in the pathogenesis of chronic intestinal inflammation. [ABSTRACT FROM AUTHOR]

Immunity to intestinal nematodes requires CD4⁺ Th2-cell responses, including IL-4 and IL-13 production. Chronic infection with intestinal nematodes leads to downregulation of these responses, and few functional T helper (Th) 2 cells are detected in secondary lymphoid organs in the chronic phase or after abrogation of infection. Here, we show with a natural murine infection with Heligmosomoides polygyrus that highly functional memory Th2 cells persist in the lamina propria and in addition in the peritoneal cavity (PC) after abrogation of infection. While both tissue-resident memory (TRM) populations proliferate in situ and express IL-4, IL-5, and IL-13 upon TCR-dependent stimulation, only peritoneal memory cells express high levels of the IL-33 receptor and produce IL-5 and IL-13 upon TCR-independent stimulation with IL-33 and IL-7. Most importantly, PC-derived TRM cells are able to mediate anti-helminthic effects by decreasing the fecundity of female worms upon transfer into recipient mice. These results show that nonlymphoid compartments can serve as reservoirs for Th2 memory cells, and furthermore that innate effector function of Th2 memory cells is restricted to CD4⁺ memory T cells residing in the PC. [ABSTRACT FROM AUTHOR]

Foxp3 specifies the Treg cell lineage and is indispensable for immune tolerance. Accordingly, rare Foxp3 mutations cause lethal autoimmunity. The mechanisms precipitating more prevalent human autoimmune diseases are poorly understood, but involve a combination of genetic and environmental factors. Many autoimmune diseases associate with a partial Treg-cell dysfunction, yet mouse models reflecting such complex pathophysiological processes are rare. Around 95% of Foxp3+ Treg cells can be specifically depleted in bacterial artifical chromosome (BAC)-transgenic Depletion of REGulatory T cells (DEREG) mice through diphtheria toxin ( DT) treatment. However, Treg-cell depletion fails to cause autoimmunity in adult DEREG mice for unclear reasons. By crossing Foxp3GFP knock-in mice to DEREG mice, we introduced additional genetic susceptibility that does not affect untreated mice. Strikingly, DT treatment of DEREG × Foxp3GFP mice rapidly causes autoimmunity characterized by blepharitis, tissue damage, and autoantibody production. This inflammatory disease is associated with augmented T-cell activation, increased Th2 cytokine production and myeloproliferation, and is caused by defective Treg-cell homeostasis, preventing few DT-insensitive Treg cells from repopulating the niche after Treg-cell depletion. Our study provides important insights into self-tolerance. We further highlight DEREG × Foxp3GFP mice as a model to investigate the role of environmental factors in precipitating autoimmunity. This may help to better understand and treat human autoimmunity. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLR) control the activation of dendritic cells that prime CD4 + T cells in draining lymph nodes, where these T cells then undergo massive clonal expansion. The mechanisms controlling this clonal T cell expansion are poorly defined. Using the CD4 + T cell-mediated disease experimental autoimmune encephalomyelitis (EAE), we show here that this process is markedly suppressed when TLR9 signaling is increased, without noticeably affecting the transcriptome of primed T cells, indicating a purely quantitative effect on CD4 + T cell expansion. Addressing the underpinning mechanisms revealed that CD4 + T cell expansion was preceded and depended on the accumulation of neutrophils in lymph nodes a few days after immunization. Underlying the importance of this immune regulation pathway, blocking neutrophil accumulation in lymph nodes by treating mice with a TLR9 agonist inhibited EAE progression in mice with defects in regulatory T cells or regulatory B cells, which otherwise developed a severe chronic disease. Collectively, this study demonstrates the key role of neutrophils in the quantitative regulation of antigen-specific CD4 + T cell expansion in lymph nodes, and the counter-regulatory role of TLR signaling in this process., (© 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Immunity to intestinal nematodes requires CD4⁺ Th2-cell responses, including IL-4 and IL-13 production. Chronic infection with intestinal nematodes leads to downregulation of these responses, and few functional T helper (Th) 2 cells are detected in secondary lymphoid organs in the chronic phase or after abrogation of infection. Here, we show with a natural murine infection with Heligmosomoides polygyrus that highly functional memory Th2 cells persist in the lamina propria and in addition in the peritoneal cavity (PC) after abrogation of infection. While both tissue-resident memory (T RM ) populations proliferate in situ and express IL-4, IL-5, and IL-13 upon TCR-dependent stimulation, only peritoneal memory cells express high levels of the IL-33 receptor and produce IL-5 and IL-13 upon TCR-independent stimulation with IL-33 and IL-7. Most importantly, PC-derived T RM cells are able to mediate anti-helminthic effects by decreasing the fecundity of female worms upon transfer into recipient mice. These results show that nonlymphoid compartments can serve as reservoirs for Th2 memory cells, and furthermore that innate effector function of Th2 memory cells is restricted to CD4⁺ memory T cells residing in the PC., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)