Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology

de, Marcela Montes; Kumar, Rajiv; Rivera, Fabian de Labastida; Amante, Fiona H.; Sheel, Meru; Faleiro, Rebecca J.; Bunn, Patrick T.; Best, Shannon E.; Beattie, Lynette; Ng, Susanna S.; Edwards, Chelsea L.; Müller, Werner; Cretney, Erika; Nutt, Stephen L.; Smyth, Mark J.; Haque, Ashraful; Hill, Geoffrey R.; Sundar, Shyam; Kallies, Axel; Engwerda, Christian

doi:10.1371/journal.ppat.1005398

Cited by 94 publications

(170 citation statements)

References 87 publications

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“…These cells in murine and human peripheral blood can be sorted as CD4 + CD49b + LAG3 + T cells (17), enabling their recognition by FACS. This phenotype cannot be used to detect Tr1 cells by immunohistochemistry, although they can be detected by double immunological staining (28,29).…”

Section: Discussionmentioning

confidence: 99%

Peripheral Tr1 and Foxp3+ Treg as Markers of Recurrent Malignancies in Patients with Hepato-Biliary Pancreatic Cancers

Ikemoto

Shimada

Ishikawa

et al. 2017

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Abstract. Background Foxp3 + regulatory T cells (Foxp3 + Tregs) play an important role in tumor immunity (1-3). Populations of peripheral Foxp3 + Tregs were found to be greater in pancreatic cancer patients than in healthy controls, with peripheral Foxp3 + Treg populations strongly correlating with TMN classifications (4). In addition, peripheral Foxp3 + Treg populations were found to significantly correlate with the pathological aggressiveness of intraductal papillary mucinous neoplasms (IPMNs), a correlation dependent on Notch signaling (5). Although Treg populations have been reported to be higher in peritumoral lesions and in draining lymph nodes, the precise mechanism underlying the increase in peripheral Tregs in cancer patients has not been determined (6, 7).Treg expansion following organ transplantation has been reported to depend on indoleamine 2, 3-dioxygenase (IDO) activity of dendritic cells (DCs) (8). IDO is a critical enzyme for maintaining pregnancy (9) and plays an important role in tumor immunity (10,11). An investigation of the associations of IDO with IPMN aggressiveness and Treg immunity showed that Treg increases induced by IDO + DCs are associated with peritumoral lesions (12). However, the mechanism underlying the expansion of Tregs in peripheral blood, as well as in the peritumoral environment, remains unclear. Tregs are easily influenced by other factors that alter host immunology, such as infection and chemo/radiation therapy, suggesting the need for more precise and stable immunological parameters to evaluate tumor immunity, especially after surgery.CD4 + CD49b + LAG3 + regulatory T cells (type 1 regulatory T cells, or Tr1s) were recently reported to have strong regulatory activities in autoimmune diseases (13). Tr1s were originally found in the peripheral blood of patients with severe combined immunodeficiency and long-term mixed chimerism after human leukocyte antigen (HLA)-mismatched fetal liver hematopoietic stem cell transplantation (14). The primary 5541

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Section: Discussionmentioning

confidence: 99%

Peripheral Tr1 and Foxp3+ Treg as Markers of Recurrent Malignancies in Patients with Hepato-Biliary Pancreatic Cancers

Ikemoto

Shimada

Ishikawa

et al. 2017

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“…Importantly, loss of TIGIT results in hyperproliferative and inflammatory T cell responses and a marked reduction in IL-10 9,14 . IL-10 itself is a key regulator of immune responses during infections, where it plays a two-sided role by both promoting pathogen persistence [17][18][19] as well as limiting excessive Th1 and CD8 + T cell responses that cause immune pathology 20,21 . Incidentally, many chronic or latent human viruses have evolved to encode IL-10 homologs in order to evade immune control 22 .…”

mentioning

confidence: 99%

TIGIT limits immune pathology during viral infections

et al. 2020

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Co-inhibitory pathways have a fundamental function in regulating T cell responses and control the balance between promoting efficient effector functions and restricting immune pathology. The TIGIT pathway has been implicated in promoting T cell dysfunction in chronic viral infection. Importantly, TIGIT signaling is functionally linked to IL-10 expression, which has an effect on both virus control and maintenance of tissue homeostasis. However, whether TIGIT has a function in viral persistence or limiting tissue pathology is unclear. Here we report that TIGIT modulation effectively alters the phenotype and cytokine profile of T cells during influenza and chronic LCMV infection, but does not affect virus control in vivo. Instead, TIGIT has an important effect in limiting immune pathology in peripheral organs by inducing IL-10. Our data therefore identify a function of TIGIT in limiting immune pathology that is independent of viral clearance.

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“…However, Tr1 cells were also found to contribute to IL-10 production, and another study showed that Tr1 cells were the main source of IL-10 in the spleen of VL patients 152 . We also find Tr1 cells to be the predominant source of IL-10 in murine VL 37 . It is becoming more apparent that multiple mechanisms feed into IL-10 production by Tr1 cells.…”

Section: Treg and Tr1 Cellssupporting

confidence: 57%

“…Macrophages are a relevant source of IL-10 during leishmaniasis; macrophage derived IL-10 has been demonstrated to impair parasite control in cutaneous leishmaniasis by autoregulating production of IL-12 and TNFα, which are critical for parasite clearance 177 . We also find that IL-10 prevents parasite control in VL, but protects macrophages from TNFα mediated death in a similar manner 37 . As with malaria, it may be possible to manipulate IL-10 producing cells to alter disease outcome.…”

Section: Il-10supporting

confidence: 57%

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Characterisation of anti-parasitic CD4+ T cell responses during malaria

Edwards¹

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1 AbstractThe CD4 + T cell response during malaria is critical for control of Plasmodium infection.Unfortunately, this response is commonly dysfunctional or absent in individuals living in malaria endemic regions, and current vaccination efforts have been unable to effectively overcome these short comings. Therefore, a better understanding of host immune responses during Plasmodium infection is required if we are to improve vaccine efficacy and promote long-lived protective immunity. To improve our understanding of the CD4 + T cell response, we assessed changes in the transcriptional profile of these cells, over the course of Plasmodium falciparum infection, in volunteers who had not previously been exposed toPlasmodium, who were taking part in controlled human malaria infection (CHMI) studies.Bioinformatic analysis identified CXCL8 expression as a biomarker of sub-microscopic infection. Additionally, the degree of CXCL8 expression was indicative of initial parasite growth rate. We also identified the emergence of a significant regulatory profile in the CD4 + T cell population which developed with drug-mediated clearance of infection. This profile included checkpoint inhibitors PD-1, LAG-3, TIM-3, and CTLA-4. The degree of PD-1 expression on putative Tr1 (CD49b+ LAG-3+) cells negatively correlated with initial parasite growth rate. However, only PD-1 blockade affected antigen specific expression of the Tr1 cell related cytokines IFNγ and IL-10 by peripheral blood mononuclear cells (PBMCs) from CHMI study volunteers. Another transcriptional change following drug-mediated control was down-regulation of the master transcription factor BACH2. BACH2 plays an important role in T cell homeostasis and facilitates the stability and function of the FOXP3 + regulatory T (Treg) cell population while modulating effector T cell differentiation. Using transgenic mice with T cell specific BACH2 deficiency we showed that BACH2 was an important intrinsic factor in CD4 + T cells during cell differentiation in vitro. In the context of experimental malaria and a second parasitic infection, visceral leishmaniasis (VL), we showed that T cell-specific BACH2 modulated Th2, Th17 and Tfh cell differentiation, and suppressed effector CD4 + T cell responses. However, BACH2 was also important for the expansion and/or maintenance of splenic Treg cells during parasitic infection. Using pathway analysis to further assess the Plasmodium induced change in the transcriptional profile of CD4 + T cells we identified differential regulation of the IL-10 Abstract 42325972 2 signalling pathway after drug-mediated clearance of infection. In a number of parasitic infections, IL-10 signalling is primarily mediated by a FOXP3 -IL-10-producing regulatory CD4 + T (Tr1) cell subset. Tr1 cell frequency has been positively correlated with chronic malaria exposure in Ugandan children, and in mouse models of VL and malaria. We recently reported that Tr1 cells suppressed anti-parasitic immune responses, but also played a key role in preventing immunopathology. To i...

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Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology

Cited by 94 publications

References 87 publications

Peripheral Tr1 and Foxp3+ Treg as Markers of Recurrent Malignancies in Patients with Hepato-Biliary Pancreatic Cancers

Peripheral Tr1 and Foxp3+ Treg as Markers of Recurrent Malignancies in Patients with Hepato-Biliary Pancreatic Cancers

TIGIT limits immune pathology during viral infections

Characterisation of anti-parasitic CD4+ T cell responses during malaria

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