Date Published: January 14, 2016
Publisher: Public Library of Science
Author(s): 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, Phillip Scott.
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.
TNF is a key pro-inflammatory cytokine required to control intracellular pathogens and kill tumours . However, excessive TNF production can cause diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, ankylosing spondylitis, graft-versus-host disease and sepsis [2,3]. As such, TNF is a major target for the prevention of inflammatory diseases, and inhibitors of TNF activity are widely used in the clinic [3,4]. An important drawback to this approach is that it can increase susceptibility to infection, especially intracellular pathogens [5,6]. Therefore, a better understanding of how TNF is regulated during inflammation is needed to identify more selective ways to control disease while minimizing risk of infection.
Here we show that Blimp-1 mRNA was elevated in CD4+ T cells from VL patients, along with IL-10 mRNA and elevated levels of plasma IL-10. Furthermore, in an experimental model of VL, Blimp-1-dependent IL-10 produced by Tr1 cells acted on myeloid cells to limit parasite killing, but was critical to prevent TNF-mediated tissue disruption. In the absence of IL-10 production by T cells, MZM were lost and this was associated with disrupted lymphocyte trafficking and splenomegaly. Thus, we have identified Tr1 cells as potent suppressors of anti-parasitic immunity, but critical regulators of IFNγ-dependent, TNF-mediated pathology.