Germinal centers: Hubs for generation of long-term immune protection

When we think about the protective mechanisms our body utilizes to protect us against infections, the first thought is our immune system. There are two main aspects of the immune system, 1) the innate immune response and 2) the adaptive immune response. The innate immune response is comprised of cells that will localize to sites of infection or injury to aid in immediate protection or clearance of harmful pathogens. The adaptive immune response is longer acting and often occurs over a period of time surpassing the infection period. However, the output of the adaptive immune response allows for immediate and precise protection during subsequent infections. For example, when you receive a vaccine for the flu, you may still get infected by the flu virus, but your body has a mechanism which can target the flu virus and aid in clearing it from your system more rapidly than if you had never had the flu or had been vaccinated. Two important cells that are part of your adaptive immune response are antibody secreting cells (ASCs) and memory B cells. The role of antibody secreting cells is to produce antibodies, which are proteins that can recognize pathogens/pathogenic proteins or infected cells and “tag” them for elimination. The antibodies produced by ASCs are very specific and will recognize very precise parts of proteins. While this provides great protection, it can be difficult when pathogens can mutate and change, such as the flu virus, in which case memory B cells will provide protection. If memory B cells can recognize a pathogenic protein, they will change into ASCs. The difference is that ASCs coming from memory B cells produce antibodies that recognize broader sequences from target proteins, allowing for broader protection when reinfected. When considering how to effectively establish these protective cells, we have to examine the source. In this case, ASCs and memory B cells are an output of the germinal center.

What is the germinal center?

The germinal center is a structure that forms in secondary lymphoid organs, such as your lymph nodes, in which B cells can proliferate and undergo class switch recombination, somatic hypermutation, selection, and differentiation. 1) B cells in the germinal centers go through cycles of cell proliferation and cell death, with a turnover rate of germinal center B cells being every six hours. 2) During the germinal center reaction, B cells can undergo class switch recombination (CSR), which allows for mutations in the constant region of the BCR to occur. When secreted or in its soluble form, the BCR are the antibodies produced by B cells. There are different classes of antibodies, including IgD, IgM, IgG, IgA, and IgE. IgD is primarily found on the surface of naïve B cells which have not previously encountered any target or pathogenic proteins, however upon activation and CSR, B cells can now produce the other antibody types including IgM, IgG, IgA, and IgE. 3) B cells can also accumulate mutations in the variable region of the BCR, a process known as somatic hypermutation (SMH), which is the part of the BCR that will recognize and bind the target protein. Accumulation of these mutations may promote the BCR to bind with higher affinity, however, it could also result in lower binding affinity. 4) Within the germinal center, not all B cells will make it out. B cells are selected for their ability to recognize the target protein, therefore if SMH leads to a BCR with lower binding affinity, that B cell will be selected to go through cell death, while a cell that has appropriate binding affinity to the target protein will be selected for survival. 5) B cells selected for survival could either continue undergoing the cycles of the germinal center and further maturation or they can differentiate into either memory B cells or ASCs.

How does a germinal center form?

B cells in secondary lymphoid organs can become activated if they can recognize a protein through their B cell receptor (BCR) and can then proceed to interact with helper T cells that provide signals, including cytokines (e.g. Interleukin-21 and interleukin-4) and ligands (CD40L) that promotes their differentiation into germinal center B cells. Differentiation into germinal center B cells is dictated by the expression of Bcl-6 (B-cell lymphoma 6). Bcl-6 is a transcription factor, which is a protein that targets specific genes for either their expression or their suppression. This in turn will determine the characteristics of these B cells that will allow them to form and maintain the germinal center, such as their ability to mutate or have a DNA-damage response, survive, and go through the different phases of the cell cycle during their proliferation.

Who participates in the germinal center?

The focus of the germinal center is for B cells to undergo a series of reactions that allow the production of memory B cells and ASCs, however, B cells do not work alone within the germinal center. For B cells to even begin forming the germinal center they require T cell help. Within the germinal center there is a specialized subset of T cells referred to a T follicular helper (TFH) cells that provide essential signals for B cells to survive, undergo CSR and SMH, and differentiate. Another T cell subset present in the germinal center are T follicular regulatory (TFR) cells, which are responsible for limiting the signals between TFH and B cells. This is a mechanism that provide regulation of the germinal center in order to avoid a hyperactive germinal center that could result in autoimmune disorders. Additionally, within the germinal center are also follicular dendritic cells (FDCs). These cells provide signals that allow B cells, TFH, and TFR cells to be maintained within the germinal center niche. FDCs are also responsible for the selection process of B cells, as FDCs can present the target proteins to B cells and determine if B cells can recognize the protein. Tingible body macrophages (TBMs) are also part of the pool of cells found in the germinal center. As previously stated, cell death is a common phenomenon within the germinal center, therefore, TBMs provide a mode of clearance of the dead cells.

In conclusion, understanding germinal centers is critical for determining mechanisms needed to generate ASCs and memory B cells with optimal function for protection. Knowledge of these mechanisms can provide targets to produce vaccines with higher efficacy or can also aid in establishing targets for therapeutic treatments in diseases that are prominent in hosts with hyperactive germinal centers. Just as germinal centers can provide ASCs that produce protective antibodies, germinal centers can also produce ASCs that secrete antibodies against self-proteins, therefore resulting in autoimmune diseases. In this case, understanding germinal centers can aid in finding targets to limit germinal center activity.

References:

1.     Stebegg, M., Kumar, S. D., Silva-Cayetano, A., Fonseca, V. R., Linterman, M. A., & Graca, L. (2018). Regulation of the Germinal Center Response. Frontiers in immunology, 9, 2469. https://doi.org/10.3389/fimmu.2018.02469

2.     Victora, G. D., & Nussenzweig, M. C. (2022). Germinal Centers. Annual review of immunology, 40, 413–442. https://doi.org/10.1146/annurev-immunol-120419-022408

3.     Basso, K., & Dalla-Favera, R. (2010). BCL6: master regulator of the germinal center reaction and key oncogene in B cell lymphomagenesis. Advances in immunology, 105, 193–210. https://doi.org/10.1016/S0065-2776(10)05007-8

4.     Mayer, C. T., Gazumyan, A., Kara, E. E., Gitlin, A. D., Golijanin, J., Viant, C., Pai, J., Oliveira, T. Y., Wang, Q., Escolano, A., Medina-Ramirez, M., Sanders, R. W., & Nussenzweig, M. C. (2017). The microanatomic segregation of selection by apoptosis in the germinal center. Science (New York, N.Y.), 358(6360), eaao2602. https://doi.org/10.1126/science.aao2602

Assessed and Endorsed by the MedReport Medical Review Board