Role of Aryl Hydrocarbon Receptor (AhR) in the Regulation of Immunity and Immunopathology During Trypanosoma cruzi Infection

INSFRAN, CONSTANZA; SERRA, HORACIO MARCELO; MOTRÁN, CLAUDIA CRISTINA; AMBROSIO, LAURA FERNANDA; RODRIGUEZ, EVA ACOSTA; CERVI, LAURA; VOLPINI, XIMENA; QUINTANA, FRANCISCO J.

FRONTIERS IN IMMUNOLOGY

Frontiers

Año: 2019 vol. 10

Resistance to Trypanosoma cruzi infection is dependent on a rapid induction ofTh1-type and CD8+ T cell responses that should be promptly balanced to preventimmunopathology. T. cruzi-infected B6 mice are able to control parasite replicationbut show a limited expansion of Foxp3+regulatory T (Treg) cells that results in theaccumulation of effector immune cells and the development of acute liver pathology.AhR is a ligand-activated transcription factor that promotes Treg cell development andsuppression of pro-inflammatory cytokine production in dendritic cells, altering the courseof adaptive immune response and the development of immunopathology. Here, we useddifferent AhR-dependent activation strategies aiming to improve the Treg response, andB6 congenic mice carrying a mutant AhR variant with low affinity for its ligands (AhRd) toevaluate the role of AhR activation by natural ligands during experimental T. cruzi infection.The outcome of TCDD or 3-HK plus ITE treatments indicated that strong or weakAhR activation before or during T. cruzi infection was effective to regulate inflammationimproving the Treg cell response and regularizing the ratio between CD4+ CD25- toTreg cells. However, AhR activation shifted the host-parasite balance to the parasitereplication. Weak AhR activation resulted in Treg promotion while strong activationdifferentially modulated the susceptibility and resistance of cell death in activated T andTreg cells and the increase in TGF-b-producing Treg cells. Of note, T. cruzi-infected AhRdmice showed low levels of Treg cells associated with strong Th1-type response, lowparasite burden and absence of liver pathology. These mice developed a Treg- andTr1-independent mechanism of Th1 constriction showing increased levels of systemicIL-10 and IL-10-secreting CD4+ splenocytes. In addition, AhR activation induced byexogenous ligands had negative effects on the development of memory CD8+ T cellsubsets 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.