Early Life B-cell and plasma cell development in the human Spleen: a new paradigm for lifelong immunity

/ABSTRACT: In ongoing experiments, we show that early-life antibody-secreting cells (ASCs), or plasma cells (PCs), appear spontaneously in the spleen, not the bone marrow (BM), before birth. The splenic ASCs develop from transcriptionally distinct fetal B-progenitors absent in adults. The splenic ASCs develop spontaneously in utero and secrete public natural antibodies (NAb) highly shared across individuals. Notably, these naturally occurring splenic ASCs secrete public NAbs with specificities against self, commensals, and common pathogens, including encapsulated bacteria known to cause life-threatening infections in infants. Finally, the naturally occurring ASCs upregulate survival genes similar to the long-lived plasma cells (LLPCs), suggesting they persist throughout adulthood. These findings highlight the relevance of the spleen, separate from the BM, in supporting the development and survival of B cells, ASCs, and NAbs that are protective against common pathogens. We validated these findings using humanized mice and showed that fetal B-progenitors give rise to long-lived mature B cells that survive >1 year and spontaneously differentiate into ASCs in the mouse spleen, not BM, and secrete public NAbs that recapitulate the specificity of the shared clones in the human fetal spleen. Here, we will characterize early-life B-cell and ASC development and function (and compare them to their adult counterparts) to uncover the mechanisms of adaptive immunity operating at birth. This will provide a new framework for understanding human immune responses at different ages and reveal new targets to modulate such responses. In three Specific Aims, we will test our hypothesis that the human immune system comprises at least two developmentally and functionally distinct lineages (or layers) of B cells and ASCs— early-life and adult. Aim 1 will focus on the B-cell development at different hematopoietic organs (liver and BM) and determine the main cytokines and metabolic dependencies that regulate B cells in early life versus adulthood. Aim 2 will characterize the phenotype and functions of the mature B-cell subsets and their spontaneous differentiation to ASCs in the spleen before birth. This aim will reveal the mechanisms of B-cell activation and metabolic reprogramming that lead to effector B cells, ASCs, and NAbs in early life. Finally, Aim 3 will focus on the antigen specificity and effector functions (glycosylation profile) of the public NAb repertoire that spontaneously emerge in the spleen before birth. We will clone the top (> 500) antibody repertoire shared across individuals to test their specificity against common pathogens, commensals, and self-antigens and search for these clones in the adult spleen. These studies will greatly extend our knowledge of the B-cell and antibody responses before birth and establish the human spleen, separate from the BM, as a unique reservoir for the development and survival of public B cells, ASCs, and functionally glycosylated NAbs against self, commensals, and pathogens known to cause life-threatening infections in children. Project Number: 1R01AI182276-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Eliver Ghosn | Institution: EMORY UNIVERSITY, ATLANTA, GA | Award Amount: $778,829 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 IIDA-Y (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18227601A1