Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells

Abstract

The variable efficacy of Bacille Calmette Guerin (BCG) vaccination against tuberculosis has prompted efforts to improve the vaccine. In this study, we used autophagy to enhance vaccine efficacy against tuberculosis in a mouse model. We examined the effect of autophagy on the processing of the immunodominant mycobacterial antigen Ag85B by antigen presenting cells (APCs), macrophages and dendritic cells (DCs). We found that rapamycin-induced autophagy enhanced Ag85B presentation by APCs infected with wild-type Mycobacterium tuberculosis H37Rv, H37Rv-derived DeltafbpA attenuated candidate vaccine or BCG. Furthermore, rapamycin enhanced localization of mycobacteria with autophagosomes and lysosomes. Rapamycin-enhanced antigen presentation was attenuated when autophagy was suppressed by 3-methyladenine or by small interfering RNA against beclin-1. Notably, mice immunized with rapamycin-treated DCs infected with either DeltafbpA or BCG showed enhanced T helper type 1-mediated protection when challenged with virulent Mycobacterium tuberculosis. Finally, overexpression of Ag85B in BCG induced autophagy in APCs and enhanced immunogenicity in mice, suggesting that vaccine efficacy can be enhanced by augmenting autophagy-mediated antigen presentation.

mTOR as a multifunctional therapeutic target in HIV infection

“…These studies show that a pathogenic microorganism can impair autophagy in non-infected cells by activating counter-regulatory pathways, and that activation of mTOR is involved in this process. In agreement with these findings it has also been demonstrated in dendritic cells (DCs) that rapamycin-mediated autophagy induction exerts a better anti-BCG vaccine response [31]. This raises the possibility of therapeutic manipulation of cell signalling to restore autophagy in HIV-1 infection [30].…”

Sensing of mammalian IL-17A regulates fungal adaptation and virulence

“…Autophagy is an evolutionary conserved response to stress that has been linked to important protective roles in mammalian cells 36 . In mammalian host-pathogen interactions, the role of autophagy has mostly favoured the host, as induction of autophagy was found to be crucial in the control of some infecting pathogens and in the ensuing immune response 37,38 . This study highlights how the TOR nutrient sensing pathway could be exploited by fungi to sense host IL-17A for survival in an immunologically reactive environment, consistent with the view that Th17 immunity develops to maintain mutualism 39 .…”

Intersection of autophagy with pathways of antigen presentation

“…Interestingly, numerous examples exist of self and foreign intracellular antigens that are presented by MHCII molecules (Nimmerjahn et al, 2003;Dorfel et al, 2005;Paludan et al, 2005;Schmid et al, 2007;Riedel et al, 2008;Jagannath et al, 2009). How do these antigens access endosomal MHCII loading compartments (termed MIIC)?…”

“…Fusing influenza matrix protein 1 (MP1) to LC3 targets MP1 to autophagosomes and improves MP1 presentation to, and activation of, antigen-specific CD4 + T cells (Schmid et al, 2007). Furthermore, upregulation of autophagy with rapamycin in murine macrophages and CD11c + conventional DC (cDC) infected with Mycobacterium tuberculosis (MTb) increases MHCII antigen presentation of the MTb secreted antigen, Ag85B (Jagannath et al, 2009). Vaccination of mice with rapamycin-treated, MTb-infected cDC enhances primary antigen-specific CD4 + T cell responses and upon challenge with MTb, recipients from the rapamycin-treated group mount superior CD4 + T cell responses and have lower bacterial loads compared to the untreated controls (Jagannath et al, 2009).…”

“…Furthermore, upregulation of autophagy with rapamycin in murine macrophages and CD11c + conventional DC (cDC) infected with Mycobacterium tuberculosis (MTb) increases MHCII antigen presentation of the MTb secreted antigen, Ag85B (Jagannath et al, 2009). Vaccination of mice with rapamycin-treated, MTb-infected cDC enhances primary antigen-specific CD4 + T cell responses and upon challenge with MTb, recipients from the rapamycin-treated group mount superior CD4 + T cell responses and have lower bacterial loads compared to the untreated controls (Jagannath et al, 2009). Together, these results demonstrate that access to, and enhancement of, the autophagy pathway upon infection can improve immune responses.…”