Role of Aryl Hydrocarbon Receptor (AhR) in the Regulation of Immunity and Immunopathology During Trypanosoma cruzi Infection
Resistance to infection is dependent on a rapid induction of Th1-type and CD8+ T cell responses that should be promptly balanced to prevent immunopathology. -infected B6 mice are able to control parasite replication but show a limited expansion of Foxp3+regulatory T (Treg) cells that results in the...
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Veröffentlicht in: | Frontiers in immunology 2019-03, Vol.10, p.631-631 |
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Zusammenfassung: | Resistance to
infection is dependent on a rapid induction of Th1-type and CD8+ T cell responses that should be promptly balanced to prevent immunopathology.
-infected B6 mice are able to control parasite replication but show a limited expansion of Foxp3+regulatory T (Treg) cells that results in the accumulation of effector immune cells and the development of acute liver pathology. AhR is a ligand-activated transcription factor that promotes Treg cell development and suppression of pro-inflammatory cytokine production in dendritic cells, altering the course of adaptive immune response and the development of immunopathology. Here, we used different AhR-dependent activation strategies aiming to improve the Treg response, and B6 congenic mice carrying a mutant AhR variant with low affinity for its ligands (AhRd) to evaluate the role of AhR activation by natural ligands during experimental
infection. The outcome of TCDD or 3-HK plus ITE treatments indicated that strong or weak AhR activation before or during
infection was effective to regulate inflammation improving the Treg cell response and regularizing the ratio between CD4+ CD25- to Treg cells. However, AhR activation shifted the host-parasite balance to the parasite replication. Weak AhR activation resulted in Treg promotion while strong activation differentially modulated the susceptibility and resistance of cell death in activated T and Treg cells and the increase in TGF-β-producing Treg cells. Of note,
-infected AhRd mice showed low levels of Treg cells associated with strong Th1-type response, low parasite burden and absence of liver pathology. These mice developed a Treg- and Tr1-independent mechanism of Th1 constriction showing increased levels of systemic IL-10 and IL-10-secreting CD4+ splenocytes. In addition, AhR activation induced by exogenous ligands had negative effects on the development of memory CD8+ T cell subsets while the lack/very weak activation in AhRd mice showed opposite results, suggesting that AhR ligation restricts the differentiation of memory CD8+T cell subsets. We propose a model in which a threshold of AhR activation exists and may explain how activation or inhibition of AhR-derived signals by infection/inflammation-induced ligands, therapeutic interventions or exposure to pollutants can modulate infections/diseases outcomes or vaccination efficacy. |
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ISSN: | 1664-3224 1664-3224 |
DOI: | 10.3389/fimmu.2019.00631 |