Naïve T and B lymphocytes undergo extensive metabolic changes during their differentiation to effector and memory cells, which clear the invading pathogens during primary response and provide long-term immunity upon secondary exposures. Though naïve T and B cells are in a state of metabolic quiescence, upon exposure to their cognate antigens, they rapidly alter their metabolic outputs to acquire distinct metabolic states associated with effector and memory phenotypes. During the acute phases of clonal expansion and effector differentiation, adaptive immune cells are engaged in anabolic processes and rely on aerobic glycolysis as the primary source of energy. Whereas, during memory differentiation, adaptive immune cells switch to catabolic programs which largely rely on mitochondrial oxidative phosphorylation to augment survival in a nutrient scarce environment. We aim to define the metabolic and epigenetic landscape of memory and effector (plasma cells) B cells with the ultimate goal to engineer these states for better, more efficient vaccines.
B cell differentiation to effector and memory cell fates is associated with dynamic changes in mitochondrial structure and function. Yet, how mitochondrial structure and function influences these cell-fate decisions in immune cells remains unclear. Our studies demonstrated that improved mitochondrial function actively promotes B cell memory generation, profoundly impacting immune response fidelity (BioRxiv). We are now genetically uncoupling discrete features of mitochondrial function to understand contributions of mitochondrial energy, ROS and metabolites in B cell differentiation. Finally, our recent work also highlighted unique features of distinct B cell receptor isotypes (IgM vs IgG1) in regulating metabolic outputs in B cells (Science Advances, 2025).
Our recent work centered on the BAF nucleosomal remodeling complex revealed the essential role
of Arid1a-dependent canonical BAF complex activity in regulation of germinal center B cell responses. Additionally, we made the unexpected discovery that Arid1a suppresses inflammatory gene programs while preserving germinal center B cell homeostasis (Nature immunology, 2024).
We also discovered a HMCES, an archaic DNA repair protein, in DNA double-strand break repair through the Alternative end-joining pathway in B cells (Mol Cell, 2020). Collaborating with Dr. David Schatz’s lab at Yale University, we identified HMCES’s unique role in preventing aberrant deletional events in B cells, showcasing its versatility in DNA repair (Genes and Development, 2022). HMCES has been shown to be critical for stress associated hematopoiesis and we are now elucidating mechanisms by which HMCES functions as an important gatekeeper of genomic stability in the hematopoietic compartment.
Abraham A*, Samaniego-Castruita D*, Han I, Ramesh P, Tran MT, Paladino J, Kligfeld H, Morgan RC, Schmitz RL, Southern RM, Shukla A, Shukla V. Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient germinal center B cell responses. Nat Immunol. 2024 Sep;25(9):1704-1717. doi: 10.1038/s41590-024-01920-y. Epub 2024 Aug 14. PubMed PMID: 39143398; PubMed Central PMCID: PMC12039306.
Shukla A.#, Tiwari A., Saulnier O., Hendrikse L., Hall B., Rickert RR, Taylor MD, Shukla V.# and Bagchi A.#. Enhancement of mitochondrial function fosters B cell memory and robust immune responses. BioRxiv 497040, [Preprint] June 2022, doi: https://doi.org/10.1101/2022.06.21.497040 (in revision at JCI) #co-corresponding authors
Southern RM*, Schmitz RL*, Samaniego-Castruita D, Balsells D, Han I, Ramesh P, Tran MT, Montes C, Cheong TC, Chiarle R, Abraham A, Waisman A, Rickert RC, Shukla V#, Shukla A#. IgM and IgG1 B cell receptors differentially affect B cell fates and dictate the pathogenesis of mature B cell lymphomas. Sci Adv. 2025 Aug 29;11(35):eadp9391. doi: 10.1126/sciadv.adp9391. Epub 2025 Aug 29. PubMed PMID: 40880486; PubMed Central PMCID: PMC12396334.
Shukla V., Halabelian L., Balagere S.V., Samaniego-Castruita D., Feldman D.E., Arrowsmith C.H. #, Rao A. #, Aravind L#. HMCES Functions in the Alternative End-Joining Pathway of the DNA DSB Repair during Class Switch Recombination in B Cells. Molecular Cell 2020, 77(2):384-394. PMID: 31806351. PMCID: PMC6980713. #Co-corresponding authors
Wu L., Shukla V., Yadavalli AD, Dinesh RK, Xu D., Rao A., Schatz DG. HMCES protects immunoglobulin genes specifically from deletions during somatic hypermutation. Genes and Development 2022, 36(7-8):433-450. PMID:35450882. PMCID: PMC9067404.