BLIMP-1: A NEGATIVE REGULATOR OF IFN-g in the immune response to Mycobacterium tuberculosis

ESTERMANN MA; CELANO J; BARBERO AM; HERNANDEZ DEL PINO RE; DOÑAS CUADRA C; MACHAIN M; ROSEMBLATT M; LOYOLA C; PASQUINELLI V

CABA

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

SAIC, SAIB, SAI, SAA, SOCIEDAD ARGENTINA DE BIOFÍSICA (SAB), SOCIEDAD ARGENTINA DE BIOLOGÍA (SAB), SAFE, SAFIS, SAH, SAP

Tuberculosis now ranks alongside with HIV as the leading cause of death from an infectious disease. Protective immunity against Myco- bacterium tuberculosis (Mtb) is mediated by Th1 immune response and IFN-g secretion.Blimp-1 plays key roles in many cell lineages and in early deve- lopment, promotes Th2 lineage commitment by opposing the diffe- rentiation of IFN-g-secreting Th1 cells. Overexpression of Blimp-1 in T cells attenuates Th1 cell expansion through downregulation of IFN-g.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-sti- mulation. Blimp-1 expression decreased at 4 days and showed the lowest expression after 5 days of Mtb-stimulation. Blimp1 kinetic was opposite to IFN-g; with the highest levels at 5 days of Mtb sti- mulation (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 af- ter 5 days. Interestingly, Blimp-1 expression among IFN-g produ- cing cells was reduced after 5 days of Mtb-stimulation.Finally, to evaluate if Blimp-1 directly regulates IFN-g 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 com- pared to 5 days. We did not find binding differences at -242 binding site.Taken together, our results demonstrate that Mtb stimulation regu- lates Blimp-1 expression on T cells and further suggest that Blimp-1 could act as an IFN-g repressor, trough the binding to CNS-22 site during Mtb stimulation.During the immune response against Mtb, IFN-g is regulated by epigenetic modifications. Blimp1 could be responsible to recruit his- tone modification complex to the IFN-g regulatory sites.