B Cell Biology

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Studies over this reported period focused on Goal 3: Understanding the impact of the human HPV-VLP vaccine on the human naive B cell compartment In an era of predicted recurring pandemics the ability to produce highly-effective, long-lived pathogen-specific vaccines will require understanding the characteristics of naive B cells in nonimmune individuals and the requirements for vaccines to activate these. We characterized the human naive B cell peripheral blood (PB) compartment (CD19+CD27-CD45RBMEM-CD38) that represents approximately 60% of all PB B cells and were separable into two subsets based on expression of CD73. The vast majority of naive B cells (80-90%) were CD73+ and of these the majority (60-70%) showed an anergic phenotype (IgMlowIgD+). In addition, the CD73+ naive B cell compartment contained the majority of all PB B cells expressing the inherently autoreactive VH4-34 heavy chain. Plasma blasts from younger individuals (18-30 years old) that received a flu vaccine seven days earlier showed that nearly half of IgM+ germline VH4-34 sequences had accumulated no or only a small number of somatic mutations (<.05%) suggesting that the plasma blast expressing these sequences were from recently activated anergic naive B cell that were diversifying the vaccine-specific repertoire. In contrast, in older individuals (70-100 years old) nearly all IgM+ VH4-34 sequences (>85%) had accumulated a large number of mutations (0.5-.16%) suggesting that these plasma blasts were recruited from an antigen-experienced population of B cells such as IgM+ memory B cells. These findings suggest that effective vaccines in nonimmune individuals must have the capacity to activate anergic naive B cells to somatically mutate and expand the diversity of the naive B cell repertoire. Having described the anergic characteristics of naive human B cells in nonimmune individuals and the outcome of flu vaccination on these anergic cells we are investigating the outcome of an HPV-VLP vaccine in use today in humans for the protection from HPV infections and cancer on the HPV-specific B cell compartment. In collaboration with John Schiller (NCI) we are carrying out an in-depth analysis of peripheral blood HPV-specific B cells from a cohort of individuals who received the HPV-VLP vaccine. To do so we established a highly sensitive fluorescent HPV-VLP probe to identify and isolate HPV-specific B cells. Using this tool we determined that HPV-VLP induced a large expansion of IgG+ MBCs but not of IgM+ MBCs. The IgG+ MBC compartment is composed of at least six phenotypically defined subpopulations and unexpectedly the HPV-VLP vaccine failed to induce ABCs and two additional MBC subpopulations. We plan to continue our analyses of the HPV-specific B cells in vaccinated individuals using single cell RNA-seq, Ig-seq and cell surface phenotyping and extend these studies to the generation of MBCs following COVID-19 vaccination. I retired at the end of December 2024 and the progress described was accomplished October 1- December 31, 2024.