Blimp-1: a negative regulator of ifn-γ expression in the immune -3- response to Mycobacterium tuberculosis.

ESTERMANN MARTIN; CELANO JOSEFINA; BARBERO ANGELA MARIA; HERNANDEZ DEL PINO RODRIGO EMANUEL; PASQUINELLI VIRGINIA; DOÑAS CUADRAS CRISTIAN; MACHAIN MONICA; ROSEMBLATT MARIO; LOYOLA ALEJANDRA

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Blimp-1: a negative regulator of ifn-γ expression in the immune -3- response to Mycobacterium tuberculosisTuberculosis now ranks alongside with HIV as the leading cause of death from an infectious disease. Protective immunity against Mycobacterium tuberculosis (Mtb) is mediated by Th1 immune response and IFN- secretion. Blimp-1 plays key roles in many cell lineages and in early development, promotes Th2 lineage commitment by opposing the differentiation of IFN--secreting Th1 cells. Overexpression of Blimp-1 in T cells attenuates Th1 cell expansion through downregulation of IFN-.Therefore, we evaluated Blimp-1 protein expression in PBMCs from healthy donors stimulated with Mtb at different time points. We found the highest Blimp-1 expression after 3 days of Mtb-stimulation. Blimp-1 expression decreased at 4 days and showed the lowest expression after 5 days of Mtb-stimulation. Blimp1 kinetic was opposite to IFN-with the highest levels at 5 days of Mtb stimulation (as determined by ELISA). We further studied Blimp-1 expression levels in CD3+ CD4+ T cells by flow cytometry. We observed high levels of Blimp-1 on CD4+ T cells. Moreover, Mtb- stimulation decreased Blimp-1 expression after 5 days. Interestingly, Blimp-1 expression among IFN- producing cells was reduced after 5 days of Mtb-stimulation. Finally, to evaluate if Blimp-1 directly regulates IFN- expression, we determined Blimp-1 binding to the IFNG gene regulatory sites CNS-22 and -242 by ChIP-qPCR. At CNS-22 site of IFNG gene we found higher binding of Blimp-1 at 3 days of Mtb-stimulation compared to 5 days. We did not find binding differences at -242 binding site.Taken together, our results demonstrate that Mtb stimulation regulates Blimp-1 expression on T cells and further suggest that Blimp-1 could act as an IFN- repressor, trough the binding to CNS-22 site during Mtb stimulation. During the immune response against Mtb, IFN- is regulated by epigenetic modifications. Blimp1 could be responsible to recruit histone modification complex to the IFN- regulatory sites