Sidebar: Meet Your Tiny Internal Infantry

Welcome! This is the first Immunology article in the COVID Demystified Sidebar series. Although I’m sure everyone wants to start discussing SARS-CoV-2 vaccine development and antibody testing right away, it’s important for us to understand how the immune system actually works in order to grasp these more complex topics. Today’s write-up will cover:

• The difference between “innate” and “adaptive” immunity.
• The difference between “myeloid” and “lymphoid” immune cells.

The article after this one, called “Choose Your Fighter”, will cover:

• The development of B cells, and their role in producing antibody.
• The development of T cells, and their roles in killing infected cells and helping B cells.

And of course, there will be two more articles covering:

• Why all of this is important for understanding vaccine development and antibody testing!

The immune system can be divided into the “innate” and “adaptive” arms.

Can you guess which barrier is the most important for protecting your body against pathogens?

If you said the skin, you’re absolutely right! Another key player is the mucous lining in your lungs and gut, which stop bacteria or viruses from sticking to and entering your cells. Additionally, the acidity and digestive enzymes in your stomach can help to inactivate these pathogens. All of these features are considered part of “innate” immunity.

Other essential components of innate immunity may be less obvious to the eye. When barriers such as the skin are breached, another layer of defense is incited. Many body cells possess a special class of proteins embedded in their surface and inside themselves, called pattern recognition receptors. These pattern recognition receptors will bind to microbe-associated molecular patterns (MAMPs). MAMPs are molecules commonly produced by bacteria or viruses, but are not found in the human body. Therefore, when MAMPs are recognized by pattern recognition receptors, the cells receive a signal that a foreigner has invaded.

Upon MAMP recognition, body cells will release their own set of chemical messages called cytokines and chemokines. Cytokines and chemokines have many functions, but one crucial consequence is the recruitment of specialized innate immune cells. These include neutrophils, macrophages, and dendritic cells, all of which act to swallow virus-infected cells or bacteria. These three types of phagocytes will then “digest” the pathogens using internal enzymes.

The innate immune system is absolutely crucial for initially recognizing pathogen intrusion, and can respond within minutes to hours of infection. In fact, many invertebrate organisms such as insects have been able to survive for thousands of years with only innate defenses.

In comparison, the adaptive immune response may take days or weeks to fully develop after infection. Furthermore, the deployment of innate soldiers such as dendritic cells is a prerequisite to activate the B cells and T cells that make up the adaptive arm. So why have an adaptive immune system at all? There are two key properties of B and T cells that innate immune cells do not possess:

1. Specificity. While body cells and innate immune cells recognize MAMPs that are shared by many different microbes, B and T cells will only identify molecules that are generated by the specific invading pathogen.

 For example, during SARS-CoV-2 infection, a dendritic cell might recognize a ribonucleic acid (RNA) molecule that is made by many types of viruses and will become activated. However, a B cell might identify a region of the spike protein fixed in the outer envelope of SARS-CoV-2 that is a unique motif for this virus only.

 2. Memory. B and T cells will potently protect against future infections by the same pathogen they have encountered before. If there is only one thing you learn from this article, this is it.

After responding to infection, a subset of B and T cells will go into hibernation. They will either circulate in the bloodstream, or take up residence in your body tissues. If a secondary infection occurs, these adaptive immune cells will rapidly reactivate and destroy the pathogen before it has a chance to cause disease. This is the fundamental basis of vaccines!

To summarize:

1. Innate immunity includes your body architecture that acts as a fortress against pathogens.
2. When barriers such as the skin are breached, your own body cells and specialized innate immune cells will act as frontline responders to hold off the pathogen.
3. The innate immune cells call in stronger reinforcements, which are the adaptive immune cells. These B and T cells are highly specific for the invading pathogen.
4. A subset of these adaptive immune cells will be retained in the body for a long time, giving rise to “immunological memory”.

Next up: where do immune cells come from?

Immune cells are all derived from a common precursor stem cell in the bone marrow.

To get an understanding of what dendritic cells, B cells, and T cells actually do, let’s first start with where they are born. All immune cells come from hematopoietic stem cells in your bone marrow. You can think of this as one really big family tree, which I’ve simplified in this diagram:

There are many more types of immune cells that are made in the bone marrow, but we’re going to stick with the ones I’ve shown above. A lot of the innate immune cells, such as dendritic cells and neutrophils, come from the common myeloid progenitor. In contrast, many adaptive immune cells, such as B cells and T cells, come from the common lymphoid progenitor. That’s why in academic papers or in the media, you may hear these cells being called lymphocytes.

It is very important to recognize that there are lymphocytes that are part of the innate immune response. We will not be discussing them today, but I hope to write a special article about them in the future.

You might notice in my previous diagram that the T cell and B cell have funny looking shapes on their foreheads. These are the T cell receptor (TCR) and B cell receptor (BCR) respectively. Just like pattern recognition receptors, the TCR and BCR will bind to molecules made by foreign pathogens that are not usually produced by your own body. However, unlike pattern recognition receptors, every T cell and B cell in your body will express a unique TCR and BCR. This is what allows these adaptive immune cells to respond to only very specific pathogens.

 To summarize:

1. Immune cells are all derived from a common precursor stem cell in the bone marrow.
2. Many (but not all!) myeloid cells make up the innate immune system.
3. Many (but not all!) lymphocytes make up the adaptive immune system.
4. T cells and B cells express a TCR or BCR on their surface, which are:

• Unique compared to the TCRs or BCRs on all the other T cells or B cells in your body.
• Specific for a given pathogen.

You might be wondering at this point, “When the heck are we going to get to the fun SARS-CoV-2 vaccine stuff?” I promise that all this learning will be worth it. The article after this one, called “Choose Your Fighter”, will cover how B cells and T cells use their BCRs and TCRs to defend your body. This will form the basis for why we use vaccines to “educate” or “train” these adaptive immune cells.

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