A New Understanding of Memory B Cell Generation in Bacterial Infections

We all know that when we’re sick, our immune system launches a response to help rid our bodies of the invading pathogen. But in addition to the cells generated for immediate pathogen elimination, our immune system also generates a set of cells that stick around for months to years; these cells are called memory cells¹. These long-lasting memory cells that are generated during an infection are specific for a particular pathogen, so if that same pathogen tries to invade months later, your memory cells will immediately recognize it. Once the memory cell recognizes that pathogen it can mount a robust immune response, hopefully before you even begin to feel sick. These memory cells are what mediate the protection against pathogens that is generated by vaccination¹.

There are two main types of memory cells: memory B cells and memory T cells. Memory T cells are derived from activated T cells during infection, which are responsible for cell-mediated immunity. T cells activate other immune cells upon infection, and kill cells that are infected with a pathogen. Memory B cells are derived from activated B cells, and are important for antibody secretion. Therefore B cells function as a vital part of humoral immunity, or immunity derived form macromolecules in fluid, in this case our bodily fluids. Antibodies bind pathogen to prevent it from entering your own cells, and to signal phagocytic cells (or “eater cells”) to destroy the pathogen by ingestion. When a memory B cell encounters its cognate pathogen upon secondary infection, it divides to form more B cells that begin to secrete antibodies to fight the pathogen.

There are many types of memory B cells, which differ in the type of antibody they produce. When a B cell is fighting an infection, it can undergo something called a class switch, which changes the type of antibodies it secretes. There are five main types of antibodies, aptly name isotypes, and each has a specific function. The IgG memory B cell, which secretes the IgG antibody isotype, has long been thought to be the primary contributor to our memory B cell populations. However in the past few years scientists have found that our memory B cell populations are actually more diverse than originally thought. In one recent study, scientists established an important role for another type of memory B cell generated after bacterial infection, the IgM B cell.

IgM B cells are the first B cells generated during an immune response for a specific pathogen. While some IgM B cells produce antibodies to begin to target the pathogen for destruction, other B cells begin to undergo class switching to produce other types of antibodies, like IgG. These B cells also undergo mutations in the DNA region that codes for the pathogen-binding domain on the antibody so that the pathogen can bind the antibody with a better fit; this is called affinity maturation. Therefore, it has long been thought that memory B cells that have undergone class switching and affinity maturation, like IgG memory B cells, are better suited for response to secondary infection since they bind the pathogen with higher affinity². But a study published by Yates and colleagues showed that IgM memory B cells, which don’t undergo affinity maturation, are actually a large proportion of our memory B cells generated during a bacterial infection. Furthermore, these IgM cells are required for the generation of IgG responses during secondary antigen challenge.

The Road to Unconventional Immune System Memory

            

One of the coolest parts of the human immune system is its ability to remember previous exposure to viruses, bacteria, or other foreign invaders.  This is crucial in creating effective vaccines that prevent humans from contracting potentially fatal diseases.  If an invader is remembered, the immune system can launch a highly specific attack and prevent the person from ever getting sick.  However, this memory is not well understood by scientists.  As more and more studies are completed, new information about new subsets of cell types involved in or capable of memory is being released.  For example, you may know how long it takes to drive from Philadelphia to Denver, but what good is that if you don’t know what roads to take?  This same idea can be applied to the memory function of the immune system.  It’s great that scientists know that once a person is infected, certain cell types can remember the invader, but it’s difficult to promote a memory response if it’s unknown how the response even occurs.

            

General Memory B Cell Development

A recent paper published in The Journal of Immunology explores the road to a memory response.  The two big cell types involved in the pathway they explore are T and B cells.  The T cells involved help to activate B cells, which then produce antibodies.  These are small proteins that circulate through the body are responsible for “tagging” foreign bodies, or antigens, for destruction by other immune cells or neutralizing the effect of the foreign body.  Antibodies come in different structures with different functions, and can switch structures during the development and maturation of the B cell from a naïve cell to memory cell.  The two structures the researchers look at are IgM, which are usually produced by naïve cells that haven’t switched antibody type yet, and IgG, which are usually produced by B cells that have fully matured into memory B cells.  However, recent studies have shown that there are also memory IgM B cells, but their characteristics, purpose, and development are unclear.  Immune cells are often identified and characterized by the molecules expressed on their cell surface.  Called CD markers, or cluster of differentiation, they allow scientists to give a unique expression pattern to help identify and isolate new types of immune cells.  In the quest to understand the memory IgM B cells, one of the things the authors tried to undercover was a unique CD expression pattern on these cells.  They also looked at a mouse model of human ehrlichiosis, a bacterial infection from ticks, to explore the necessity of a T cell-B cell interaction for the activation of these IgM memory cells.  The also used this model to look at a secondary exposure to an antigen and determine the connection between these new memory cells and typical IgG memory 

Newly Recognized Lung-specific Memory T Cells Afford Greater Protection Against Influenza Virus

Every year, millions of people across the world become infected by the influenza virus, resulting in an average of between 250,000 and 500,000 fatalities annually, and over $80 billion in costs in the United States alone. Current seasonal influenza vaccines consist of three different, common strains of inactivated influenza virus. These inactivated viruses cannot replicate or cause pathogenic infection, but the viral proteins are recognized by the host immune system and evoke an immune response that leads to generation of specific cells that have greater efficiency in clearing the virus upon second exposure. Current research is thus focused on potential vaccines and treatments that can augment the immune response to favor generation of cells with the best ability to clear influenza viral infection.

At the molecular level, viral flu proteins are recognized by receptors on host immune cells called dendritic cells (DCs) or other antigen-presenting cells, which present small bits of viral protein to T cells, which subsequently become “activated” and await second exposure to the virus. Some T cells with particularly high antigen-specificity (in other words, T cells with receptors that bind with optimal affinity to particular influenza viral antigen) differentiate into memory T cells, which “remember” a specific antigen and are able to produce a faster, more efficient immune response upon subsequent exposure. In this case, the memory T cells effectuate a clearance of the virus through several mechanisms, including production of proteins called cytokines, many of which induce inflammation to help clear viral infection. A specific class of T cells called helper T cells, or CD4 T cells, has been demonstrated to be particularly helpful in the immune response against viral infection because of their particular subset of secreted cytokines. A paper published just this month in The Journal of Immunology by Teijaro and colleagues describes a newly identified class of lung tissue-resident memory CD4 T cells with enhanced ability to provide protection during respiratory viral infection. The authors utilized several distinct mouse models to demonstrate T cell retention in the lung after influenza virus infection and increased protection from morbidity from the virus.

A New Take on the Importance of Memory

When you hear the word memory your initial thought may be to think of your brain.  However, the memory of cells plays an integral role in other systems of our bodies as well. Memory is crucial to the immune system’s ability to efficiently fight off infections.  Our bodies are miraculously able to generate antibodies against viruses while maintaining anti-viral antibody secreting cells to protect us from future attack by the same virus. While antibodies we make span a month, they retain the means of reproducing them for a lifetime (3).

In 1796, Edward Jenner’s noted that dairymaids and farmers lacked the smallpox that was disfiguring and killing whole villages. Cowpox during this time suffered from a similar disorder, cowpox, in which cattle experienced similar but less severe symptoms than humans (3). He exposed an 8-year-old boy first with fluid from an infected cow then two months later he inoculated the boy with smallpox. Sure enough, the boy’s immune system was able to remember how to fight the infection (3). This experiment, although clearly unethical, proved to be the first successful vaccination that would lead to the development of future vaccinations for a plethora of viruses. Jenner paved the way for future scientists to build off his idea of weakening pathogens in the laboratory to inoculate patients with in order to protect them from future exposure to that pathogen.  Today scientists continue to build off of this demonstration with the intent to better understand the cellular and molecular mechanisms governing this profound observation and experiment.