The generation of memory cells and formation of long-lived plasma cells

In this article, I briefly describe the generation of memory cells and the formation of long-lived plasma cells from B cells.

Table of Contents

Differentiation of B cells to produce memory cells

B cells undergo the process of differentiation after getting activated by T cells. They differentiate to produce plasma cells, memory cells, or activated germinal center B cells. B cells carry out many immune functions. They can present antigens and secrete regulatory cytokines. However, most importantly they produce antibodies.

The antibody-forming cells, are the first B cells to produce antibodies. They do it after encountering with antigens in the extrafollicular primary foci of the lymph nodes and the spleen. Naïve B cells do not secrete antibodies. However, antigens stimulate them to become plasmoblasts. These differentiated B cells then start to synthesize antibodies.

Naïve B cells and plasmoblasts bear cell surface receptors. Plasma cells are the differentiated B cells that can’t divide anymore. So, they bear no cell surface receptors and rapidly secrete a large number of antibodies. The coordinated expression and repression of a hundred genes is necessary for the development of a naïve B cell into an antibody-secreting plasma cell.

Plasma cells render high concentrations of specific antibodies that can opsonize antigens within the first week of an immune response. These are the major sources of protective humoral immunity early after coming in contact with antigen.

Formation of germinal centers

When the stimulated B cells enter the follicles, and encounter with antigens, they begin to divide rapidly. They undergo further differentiation, and form germinal centers. The germinal centers, along with B cells, contain follicular dendritic cells, T follicular helper cells, and macrophages.

The developing germinal center has two distinct zones, the dark zone and the light zone. The light zone is mainly populated with follicular dendritic cells. The dark zone is located very near to the T-cell zone. The B cells in the dark zone are rapidly dividing and are called centroblasts. The B cells in the light zone are less proliferative and are known as centrocytes. The division of B cells between the two zones depends upon their expression of various chemokine receptors.

T-dependent antigens recognized by memory B cells are generated both inside and outside the germinal center

The process of vaccination involves the ability of an animal to respond more quickly and effectively with the production of antibodies on the second exposure to an antigen compared to the first one. The memory B cells on the second antigenic challenge include different cell types with diverse and precise functions in the long-run maintenance of immunity.

The memory B cells come in contact with the T-dependent antigens and start differentiation to form long-lived secondary B cells. The long-lived B cells give more quicker and stronger response than primary B cells on further antigenic activation.

Two subsets of memory B cells

There are two subsets of memory B cells produced in our immune system. In the early immune response, the first subset of memory B cells are generated before the formation of the germinal center. The first subset of memory B cells consists of mainly IgM-bearing B cells with unmutated receptors. These early memory B cells continue their generation for many weeks after initial contact with antigen.

If early mutational events fail to clear the pathogen, then a pool of antigen-binding cells formed from early memory B cells enter the germinal center. The activation of this group of antigen-binding cells is hindered by the soluble antibodies as the former has a low affinity for the immunizing antigen.

Within four days of antigen encounter, the mass of memory B cells switches location to the germinal center. The germinal center is the location where mutated, high-affinity memory B cells are generated. In the germinal center, the memory B cells do not restrict themselves producing only IgM antibodies. They shift the production to other classes of antibodies, which begin to collect mutations in the variable regions.

Thus, consequently memory B cells generated early in the germinal center (approximately 6-8 days after antigen contact) have a higher number of IgM-bearing than IgG-bearing cells. They also have a lower number of mutations than the memory B cells generated later. Among the memory B cells, some stay within the germinal center. Some of them migrate to the marginal zone of the spleen and the mucosal epithelium of the tonsils, gut, and lungs.

Generation of long-lived plasma cells

Plasma cells produced in the bone marrow are long-lived and secrete antigen-specific antibodies for a long period after stimulation from antigen without any need for further antigenic stimulation. Bone marrow plasma cells have a half-life of many years. In humans, smallpox-specific serum antibodies have been marked for about more than seventy-five years after immunization with the smallpox vaccine. Thus, the antibodies stay for a lifetime within the host.

When B cells of the germinal center come in contact with antigen, they upregulate the expression of transcription factors within ten days. This drives the production of plasma cells. After the generation of regular memory cells in the germinal center, the differentiation of long-lived plasma cells begins. The formation of long-lived plasma cells depends upon the interactions between the T_FH PD-1 receptor and its ligands PD-L1 and PD-L2 on the B cells of the germinal center.

When the B cell in the germinal center differentiates into a mature plasma cell, some chemokine receptors change their expression. When a B cell is converted to a fully mature plasma cell, then the expression of the chemokine receptor CXCR5 decreases and that of CXCR4 increases. Thus, the cells exit the follicles and enter into the peripheral circulation. Among the long-lived plasma cells, around 10-20% stay in the bone marrow. Rest enters the gut and mucosal tissues of the lungs.

How do long-lived plasma cells derived from the germinal center differ from normal memory B cells?

There are some differences between the germinal center-derived long-lived plasma cells and the regular memory B cells. The immunoglobulin (Ig) genes of long-lived plasma cells have gone through somatic hypermutation and affinity maturation. Long-lived plasma cells have reduced membrane BCR expression than regular memory B cells.

Long-lived plasma cells get cytokine signals from mesenchymal stromal cells, eosinophils, and megakaryocytes within the bone marrow. The anti-apoptotic molecules like Mcl-1 are upregulated by these cytokines, thus increasing the long life span of the long-lived plasma cells. Plasma cells rely on specialized cellular metabolism like autophagy. Thus, their nutrition supply is increased.

Plasma cells and naive B cells not only differ in life span but also based on their histology, their expression of different cell surface markers and transcription factors, and their proliferative potential.

When a B cell encounters an antigen, it undergoes an asymmetric division to give one long-lived plasma cell and one memory cell. The initial cell divisions after an antigenic stimulation give rise to regular memory B cells. However, the later divisions release plasmoblasts, from which long-lived plasma cells arise.

The repeated response by memory B cells

The primary response to antigen is always weaker and slower than the later responses. Naïve B cells and memory B cells express different signaling molecules, which result in an increased rate of Ca²⁺ mobilization in IgM memory cells than in naïve B cells. It also produces an extended Ca²⁺ response in IgG memory B cells.

Due to such signaling disparity, memory B cells have an agile movement towards the entrance of the cell division cycle than naïve B cells. Transcription factors in lower concentration are required to maintain a cellular resting state. The condition is fulfilled by memory B cells. Thus, they enter more readily into the cell cycle.

Memory B cells secrete higher levels of CD40, CD80, and CD86, which mediate signaling interactions with T cells. Researchers have also established the fact that some memory B cells undergo proliferation in response to innate stimuli CpG. But naïve B cells need collateral stimulation through the BCR and toll-like receptor (TLR). This gives an idea about the innate stimuli that may play a role in the maintenance of memory B cell population.

Memory B cells and naïve B cells differ in needing help

Memory and naive B cells also differ in the requirement of aid from cells. Some virus-specific memory cells do not need any help from T cells during re-stimulation. However, most memory cells require some assistance from follicular T helper cells (T_FH) during the phase of re-stimulation.

Memory T_FH cells keep hold of a noticeable expression of the CXCR5 receptor, thus getting assembled in the follicles of lymph nodes and spleen and at the border of T cell or B cell. As the memory T_FH cells gather in the follicles, they are readily available for B-cell interaction. The maintenance of memory B cells is assisted by follicular dendritic cells (FDCs). They (FDCs) provide survival factors and serve as reservoirs of antigens.

The IgG and IgM bearing memory cells differ in repeated response to antigen

The IgG-bearing memory cells and the IgM-bearing memory cells show differences in their repeated response to antigens. They have variations in the response to their respective receptor molecules and thus have different sensitivities to serum antibodies inducing inhibition.

The presence of antigen-specific antibodies readily inhibits IgM-bearing memory B cells causing them not to give a response until after the decline in the levels of antibody. However, IgG-bearing memory cells are not so responsive to this inhibition as they are very quickly stimulated on a second encounter with an antigen.

When IgM memory cells get stimulated, they get an entry or re-entry into the germinal centers. In the germinal center, they can undergo somatic hypermutation to generate new memory cells for subsequent responses. This different approach of two types of memory cells eases the exhaustion of memory responses to the frequent attack of cross-reacting or same antigens.

It also gives a chance to the low-affinity IgM-bearing memory cells to undergo mutation in response to antigen variations. The Influenza virus mutates first giving rise to different antigenic determinants of a single infection. It gets combated by new high-affinity IgM and IgG-bearing memory cells.

Conclusion

B cells after activation by T cells, undergo differentiation to produce plasma cells and memory cells. Long-lived plasma cells are produced in the bone marrow. Memory cells undergo differentiation to form long-lived secondary B cells, which give quicker responses than primary B cells. The high-affinity memory B cells are formed in the germinal center. The primary response of memory cells to antigens is always slower and weaker than the later responses.

The IgG-bearing memory cells and the IgM-bearing memory cells show differences in their repeated response to antigens. They have variations in the response to their respective receptor molecules.