The inhibition of HIF-1α limits the migration of dendritic cells to lymph nodes in BCG-vaccinated mice

MAIO, MARIANO; JOAQUINA BARROS; ALEXIA ZUFFINETTI; MARIA FLORENCIA TODERO; ALAN BERNAL; RAFAEL J ARGÜELLO; FEDERICO BLANCO; MÓNICA VERMEULEN; LUCIANA BALBOA

Bucaramanga

Congreso; XI REUNIÓN DE LA SOCIEDAD LATINOAMERICANA DE TUBERCULOSIS Y OTRAS MICOBACTERIOSIS; 2023

Dendritic cells (DCs) are key players in the host response to the tuberculosis (TB) agent, Mycobacterium tuberculosis (Mtb), which has been shown to interfere with DC functions, delaying the onset and development of adaptive immunity. Given our prior work demonstrating the importance of HIF-1α-mediated glycolysis in the migration of Mtb-stimulated DCs into lymph nodes, herein we wondered whether the inhibition of HIF-1α in bone marrow derived- DCs (BMDCs) could have an impact on their migration to lymph nodes, limiting the induction of the adaptive immunity driven by the Bacillus Calmette-Guérin (BCG) vaccine strain. BCG-infected BMDCs showed reduced OXPHOS dependence in parallel with increased glycolytic capacity compared to uninfected cells. In addition, BCG-infected BMDCs released increased lactate levels that were suppressed by the use of PX-478 (PX), an inhibitor of HIF-1α. Thus, the BCG vaccine strain induces glycolysis in a HIF-1α-dependent manner in BMDCs. Next, BMDCs were infected with BCG in the presence or absence of PX and labeled with either CTV or CFSE. A mix of both labeled populations was transferred into naïve mice. PX treated-BCG-infected BMDCs were less efficient at reaching the lymph nodes compared to untreated BCG-infected BMDCs. Therefore, HIF-1α is required for an efficient migration of BCG-infected BMDCs to lymph nodes.To determine whether a diminished migration to lymph nodes could limit the induction of the BCG-driven Th1 immune response, we inoculated BCG-infected BMDCs treated or not with PX into naive mice. A higher number of CD3+ CD4+ IFNγ-producing cells in response to PPD were detected in splenocytes from mice that received BCG-infected BMDCs compared to those treated with PX on day 19. Nevertheless, at later times, no differences were observed. Therefore, this data indicates that the inhibition of HIF-1α in BCG-infected BMDCs leads to lower numbers of IFNγ-producing CD4+ lymphocytes specific for mycobacterial antigens at earlier time points. The development of tools aimed at enhancing the migratory capacity of DCs by promoting their HIF-1α-mediated glycolytic activity may increase the efficacy of TB preventive strategies.