Understanding the immunology of helper T cells, germinal centers, and the human naive B cell repertoire to enable better vaccine design
Most vaccines provide protection from infection through the generation of neutralizing antibodies (nAbs). The repertoire of naive B cells is the starting material from which nAbs eventually arise. Immunization strategies are increasingly targeting precise B cell specificities to mimic nAbs generated during natural infection, in an effort to maximize the potency of the vaccine-elicited Ab response. An understanding of the human B cell specificities capable of immunogen recognition can aid in immunogen design and inform decision-making for clinical trial advancement. We have developed strategies to probe for antigen-specific B cells in the human naive B cell repertoire (Science 2016, Science Translational Medicine 2018, COI 2018, and Science 2019)
Germinal centers (GCs) are the engines of affinity maturation and are the critical source of memory B cells and long-lived plasma cells. GCs are entirely dependent on T follicular helper (Tfh) CD4 T cells (Immunity 2019). Helping B cells and antibody responses is a major function of CD4+ T cells. It has been 10 years since the publication of Bcl6 as the lineage defining transcription factor for T follicular helper (Tfh) differentiation and the requirement of Tfh cells as the specialized subset of CD4+ T cells needed for germinal centers and related B cell responses. A great deal has been learned about Tfh cells in the past 10 years.
Using longitudinal tracking of GCs in draining lymph nodes, using fine needle aspirates (FNAs), we found that two independent methods of slow delivery immunization of rhesus monkeys (RM) resulted in larger GCs, more robust and sustained GC-Tfh cell responses, and GC B cells with improved Env-binding. These GC-associated cell differences correlated with the development of ~20- to 30-fold higher titers of tier 2 HIV nAbs in animals immunized via slow delivery modalities. By analyzing IgV gene usage, we were able to determine that slow delivery immunization enhances HIV neutralizing antibody and GC responses via modulation of immunodominance (Cell, 2019). Slow delivery immunization therefore engages the immune system in unique ways, and novel strategies to accomplish slow delivery immunization in human vaccines will be discussed.