Effective generation and long-term maintenance of immune memory cells are critical for the success of vaccines against pathogens. Mice with autophagy deficiency in B cells show a severe defect in the maintenance of memory B cells after immunization, and succumb to viral infections due to failure to generate protective secondary antibody responses. Autophagy is required for the long-term persistence of memory B cells to protect against viral infections. Similarly, it has been shown that autophagy is also required for the protection of memory T cells. However, the precise mechanisms for autophagy in the protection of memory B cells remain to be defined. We have found that Nix and Bnip3, two Bcl-2 family members important for mitochondrial autophagy, are required for the generation of antigen-specific memory B cells. We hypothesize that autophagy is essential for the protection of mitochondrial functions to protect the survival and functions of memory B cells. We will perform the following experiments to test this hypothesis: 1) To determine the molecular mechanisms by which Nix and Bnip3- dependent mitochondrial autophagy protects antigen-specific memory B cells. Whether defective mitochondrial autophagy in Nix- and Bnip3-deficient memory B cells leads to aberrant metabolic functions will be determined; 2) To test the hypothesis that mitochondrial autophagy protects against cell death in memory B cells. Whether disruption of mitochondrial integrity leads to the release of mitochondrial ptoteins or DNA in the induction of cell death in memory B cells; and 3) To determine the molecular mechanisms for mitochondrial autophagy in memory B cells. The functions of novel Nix- and Bnip3-interacting proteins in the regulation of mitochondrial autophagy will be studied. The findings from this study may facilitate the development of better strategies to enhance the efficacy of vaccination against infections by targeting mitochondrial autophagy.
| Sandoval, Hector; Kodali, Srikanth; Wang, Jin (2018) Regulation of B cell fate, survival, and function by mitochondria and autophagy. Mitochondrion 41:58-65 |
| Kimata, Jason T; Rice, Andrew P; Wang, Jin (2016) Challenges and strategies for the eradication of the HIV reservoir. Curr Opin Immunol 42:65-70 |
