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

Abstract

Tumor necrosis factor (TNF) is critical for controlling many intracellular infections, but can also contribute to inflammation. It can promote the destruction of important cell populations and trigger dramatic tissue remodeling following establishment of chronic disease. Therefore, a better understanding of TNF regulation is needed to allow pathogen control without causing or exacerbating disease. IL-10 is an important regulatory cytokine with broad activities, including the suppression of inflammation. IL-10 is produced by different immune cells; however, its regulation and function appears to be cell-specific and context-dependent. Recently, IL-10 produced by Th1 (Tr1) cells was shown to protect host tissues from inflammation induced following infection. Here, we identify a novel pathway of TNF regulation by IL-10 from Tr1 cells during parasitic infection. We report elevated Blimp-1 mRNA levels in CD4+ T cells from visceral leishmaniasis (VL) patients, and demonstrate IL-12 was essential for Blimp-1 expression and Tr1 cell development in experimental VL. Critically, we show Blimp-1-dependent IL-10 production by Tr1 cells prevents tissue damage caused by IFNγ-dependent TNF production. Therefore, we identify Blimp-1-dependent IL-10 produced by Tr1 cells as a key regulator of TNF-mediated pathology and identify Tr1 cells as potential therapeutic tools to control inflammation.

• Authors: Marcela Montes de Oca, Rajiv Kumar, Fabian de Labastida Rivera, Fiona H Amante, Meru Sheel, Rebecca J Faleiro, Patrick T Bunn, Shannon E Best, Lynette Beattie, Susanna S Ng, Chelsea L Edwards, Werner Muller, Erika Cretney, Stephen L Nutt, Mark J Smyth, Ashraful Haque, Geoffrey R Hill, Shyam Sundar, Axel Kallies, Christian R Engwerda
• Journal: PLoS pathogens (PLoS Pathog) Vol. 12 Issue 1 Pg. e1005398 (Jan 2016) ISSN: 1553-7374 [Electronic] United States
• PMID: 26765224 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Repressor Proteins
• Tumor Necrosis Factor-alpha
• Interleukin-10
• PRDM1 protein, human
• Positive Regulatory Domain I-Binding Factor 1

Topics

• Animals
• Disease Models, Animal
• Female
• Flow Cytometry
• Humans
• Inflammation (immunology, pathology)
• Interleukin-10 (biosynthesis, immunology)
• Leishmaniasis, Visceral (immunology, pathology)
• Malaria (immunology, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Microscopy, Fluorescence
• Positive Regulatory Domain I-Binding Factor 1
• Repressor Proteins (immunology)
• T-Lymphocytes, Regulatory (immunology)
• Th1 Cells (immunology)
• Tumor Necrosis Factor-alpha (immunology)