lesson 5.3 workbook - tufts university · b.bone marrow. c.thymus. ... after clonal expansion,...

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W o r k b o o kLesson 5.3

DEFINITIONS OF TERMS

Clone — a cluster of identical cells that orginated from a

single cell.

For a complete list of defined terms, see the Glossary.

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One cell with an antigen specific receptor is not enough to respond to an infection, so how do you make more?

As we discussed in lesson 5.2, we have billions of B and T cells with receptors that are made randomly so each cell has its own unique receptor. When B and T cells have receptors that bind an antigen they divide, while the B and T cells that do not recognize the antigen do not divide. This means that the immune system can increase the number of cells that can fight a current, specific infection. This multiplication is called clonal expansion because the division of activated B or T cells generates numerous cells that are identical — clones — to the parent B and T cells. In this way, a B cell that recognizes ‘its’ antigen will expand rapidly to increase

LESSON 5.3 WORKBOOKEvolving pathogens — our body’s responses — B and T cells

In the last lesson, we discussed how B and T cells make receptors to target a practically unlimited number of antigens by randomly cutting and pasting DNA. Here, we are going to focus on how these antigen specific cells are selected, and expanded to create an army of cells to fight infection. We will also see how lymphocytes (on the image on the right) such as B and T cells, respond to disarm and kill pathogens after they have expanded.

Figure 1: Only B or T cells that have 'met' their antigen undergo clonal selection and expansion.

http://sites.tufts.edu/greatdiseases/student/glossary/

LESSON READINGS

208


1. The cloning or division of B and T cells occur in the

.a lymph nodes.

.b bone marrow.

.c thymus.

.d any of the above.

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Lymphatic system — part of the circulatory system. One of its main functions is participating in

the immune response.

Lymph nodes — small masses of cells, spread throughout

the body, that are part of the lymphatic system. Lymphocytes and other immune cells reside in

them.

Effector cells — lymphocytes that have clonally expanded and

are primed to respond to a threat.


the number of B cells with that specific BCR. However, this takes time, which accounts for the 8–12 day delay in the onset of the adaptive immune response after it first meets a pathogen. This delay is the learning curve of adaptive immunity. After the infection has been controlled, some of the cells remain in our bodies in case we are exposed to the same pathogen again, which is the memory part of adaptive immunity.

This delay in adaptive immune response is clinically important!

Clonal expansion takes place in the lymph nodes. Have you ever felt this? A swollen lymph node in your neck is an indica-tor that you have an infection because this is where the B and T cells are dividing like mad. During the 8–12 days, it takes to develop an arsenal of clonally expanded B and T lymphocytes, it is up to the innate cells to keep the infection in check. This delay is one of the reasons a doctor may ask for how long you have been sick; most illnesses resolve when adaptive cells begin to respond, so treating with antibiotics before then may be unnecessary. If you have been sick for less than 10 days the doctor may hold off on antibiotics, to give your B and T cells time to kick in.

We will now describe how B and T cells control an infection after they have expanded

B cells release antibodies, and save the memory of a pathogen

This is how B cells work after clonal expansion: First of all, effector B cells make vast amounts of antibodies that target the pathogen. In addition, some of the expanded B cells are saved in the form of memory cells that can respond quickly, if the infection is encountered again.

Figure 3: Clonally expanded B cells turn into effector or memory cells.

Figure 2: Some of the major organs of the lymphatic system.


LESSON READINGS

209


2. The delay in adaptive immune response is clinically important. It usually takes ____ days to develop clones and expand B and T cells. If you have been sick for less, the doctor might hold off on antibiotics.

.a 3–5

.b 5–8

.c 10–12

.d 12–15 ______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________


Agglutination — the clumping of bacteria or viruses in the

when mixed with antbodies that bind to them.


But how do the secreted antibodies control an infection? Remember that antibodies are soluble versions of the BCR, and have the same antigen specificity as the original B cell that underwent clonal expansion.

Antibodies act in three main ways:

1. They neutralize the antigen by sticking to it, and preventing it from performing its function.

2. They cover the pathogen, and mark it for better phagocytosis by innate cells.

3. They activate the complement which lysis the pathogen.

Let's review in details each one of these mechanisms

Neutralization: antibodies can prevent an infection by neutralizing the pathogens's key antigens such as surface receptors or the toxins they produce. A classic example of neutralization happens for many viruses. For example, antibodies against the viral receptors can bind and block them. As seen on the image on the left, the antibodies are like birds that landed on poles, the receptors of a Rotavirus. The viral receptors are now unavailable for attaching to a host cell.

Agglutination and marking antigens for phagocytosis: Innate cells use receptors that recognize PAMPs to phagocytose pathogens. But if the pathogen mutates or hides the PAMPs, innate cells may not be able to phagocytose hem. To enhance phagocytosis, antibodies that are specific for a pathogen's antigen will bind to it, causing it to clump (this is called agglutination).

In addition, these antibodies on the surface of the pathogen also act like a bull's eye that attracts more innate cells, increasing the likelihood of phagocytosis. A good example of this is Strep. pneumoniae, which has a thick capsule that camouflages its PAMPs. Innate cells may not be able to recognize the capsule

Figure 4: Depiction of the three main ways an antibody participates in the immune response.

Figure 5: An electron microscopy image of a Rotavirus particle coated with antibodies.


LESSON READINGS

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3. Which of the following statement about how antibodies act is true?

.a They neutralize the antigen by sticking to it and preventing it from functioning.

.b They cover the pathogen and mark it for better phagocytosis.

.c They activate the complement which makes holes in the pathogen.

.d all of the above________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

but antibodies to the capsule will. After the antibodies bind to the capsule, they will cause agglutination, directing the innate cells to the bacteria so they can phagocytose them.

Activation of complement: As we discussed in lesson 1.5, the complement is a set of proteins in the blood that can lyse invading pathogens. When antibodies bind to pathogens, they also mark them for complement attack, and this results in increased lyses of the pathogen. So far, we discussed how B cells control pathogens. We will now shift our attention to T cells.

How do T cells respond to a pathogen?

First, we need to clarify that there are two main types T cells: Killer T cells and Helper T cells. In contrast to B cells that directly recognize and bind antigens circulating in the bloodstream, T cells have a unique way of recognizing their antigens — the antigen must be presented to the T cell from the surface of self-cells.

This is how it works: First (step 1 in Fig. 6), phagocytes engulf a pathogen or part of an infected host cell. The microbe is then digested and the structures are processed into small fragments (antigens). Next (step 2), these antigens are bound by specific molecules of the host (labeled 'self-protein') forming a complex. To show this to T cells, the newly formed 'self-nonself complex' moves to the surface of the host cell (step 3). Once on the cell surface, the antigen is now exposed to T cells some of which might have the perfect randomly made match to recognize the antigen (step 4). When a T cell recognizes the antigen, it will undergo clonal expansion (not shown on Fig. 6, for details review Fig. 1).

Both killer and helper T cells can recognize antigens presented by a host cell. However, their responses to the antigens differ. Killer T cells respond by killing infected self-cells. Helper T cells are often referred to as the orchestrators of the immune response because they allow B cells to make antibodies, enhance Killer T cell function, and ramp-up innate responses.

Figure 6: T cells need to be presented with an antigen by a self-cell.

LESSON READINGS

211


4. Which statement about clonal expansion is false?

.a It is needed because one adaptive cell is not enough to fight a toxin or infection.

.b B and T cells that recognize a specific antigen divide, while those that do not, do not divide.

.c Division of activated B or T cells generates numerous cells that are identical (clones of the parent).

.d It allows ‘learning’ and ‘memory’ of adaptive immunity to occur.

.e none of the above ____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________


Peptides — shorts chain of amino acids. They can be

generated when proteins are digested into small pieces,

peptides.

Apoptosis — an active process of programmed cell

death executed by the cell itself (suicide).


Killer T cells kill infected host cells and cancerous cells

All self-cells continually present digested molecules (antigens) from their cytoplasm on their surface, so killer T cells can ‘see’ them. After clonal expansion, effector killer T cells patrol the body interacting with self-cells in search of their specific antigen. This antigen may be from an intracellular infection or even abnormal peptides from defective host cells. For example, cancerous cells often make proteins that healthy cells don’t. Killer T cells 'see' these proteins when presented on the surface as foreign antigens, and mark them for destruction. Any time a Killer T cell recognizes ‘its’ antigen, whatever it is, they will respond by inducing host cell death, which in turn will block intracellular infection for once and for all. This is why they are called killer cells!

How Killer T cells kill infected host cells?

To explain the process, we will walk through the figure below:

The self-cell harboring a pathogen, presents the pathogen's antigens on its surface. In reality, each cell will present multiple different antigens that may come from different digested microbial structures. In this case, an effector killer T cell with a receptor that is specific for the antigen, binds to it, and becomes activated. The activated killer T cell secretes enzymes that are taken up by the host cell. The infected host cell responds to the enzymes by switching on its ‘suicide program’ that is called apoptosis or it can cause cell lysis. Once the cells have committed suicide, innate cells move in and phagocytose what is left, thereby removing both the dead cell, and the pathogen debris.

The same process of T cell killing takes place when a killer T cell recognizes an abnormal peptide on the surface of a cancerous cell.

Figure 7: The mechanism of action of a killer T cell once it is finds a host cells with its antigen.


LESSON READINGS

212


5. ____ make vast amounts of antibodies that target the pathogen; ____ begin to lyse infected host cells; _____ enhance B and killer T cell responses.

.a helper T cells; killer T cells; effector B cells

.b effector B cells; helper T cells; killer T cells

.c helper T cells; effector B cells; killer T cells

.d effector B cells; killer T cells; helper T cells

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Helper T cells orchestrate the immune response

After clonal expansion, effector helper T cells patrol the body in search of innate cells that present their specific peptide (antigen). If a helper T cell recognizes its peptide, it will respond by secreting cytokines and chemokines that promote the functions of effector B cells, effector Killer T cells, and activated innate cells. This widespread action is why helper T cells are thought of as orchestrators of the immune response.

The diagram on the right shows a helper T cell recognizing an antigen presented by an innate cell. The helper T cell then responds by secreting cytokines. These cytokines have four main functions:

■ They stimulate the replication of effector helper T cells.

■ They are required for antibody secretion by effector B cells.

■ They are required to fully activate effector killer T cell killing.

■ They activate innate cells and cause chemotaxis (not shown on this diagram), again amplifying the immune response.

Because Helper T cells are required for the full response of B cells, killer T cells, and innate cells, their removal is extremely detrimental to the host. For example, when HIV infects helper T cells (also called CD4) it leads to their destruction, which in turn compromises killer T cell function and antibody responses, leaving the host little protection against other pathogens.

Like B cells, some of the activated T cells are saved as memory cells that can respond quickly if the infection is encountered again. Both memory B and T cells can be saved for decades, and respond quickly if the infection returns because they won’t need to clonally expand. This property of the immune system is the basis of immunization, which we will learn more about in the next lessons.

Figure 8: After a helper T cell is presented with an antigen, it secretes cytokines that can perform different actions.

STUDENT RESPONSES

213


Remember to identify your sources

What happens if you are exposed to the same pathogen for a second time in your life?

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Draw a flow chart to describe what happens when an individual B cell recognizes an antigen.

STUDENT RESPONSES

214


Remember to identify your sources

Indicate what happens when an individual killer T cells responds to an antigen.

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Indicate what happens when a helper T cell responds to an antigen.

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Which type(s) of immune cell would recognize a toxin?

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Which type(s) of immune cell would recognize a cell infected with chlamydia?

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Which type(s) of immune cell would recognize a cell infected with HIV?

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TERMS

215


TERM DEFINITION

Agglutination The clumping of bacteria or viruses in the when mixed with antibodies that bind to them.

Apoptosis An active process of programmed cell death executed by the cell itself (suicide).

Clone A cluster of identical cells that originated from a single cell.

Effector cells Lymphocytes that have clonally expanded and are primed to respond to a threat.

Lymph nodes Small masses of cells, spread throughout the body, that are part of the lymphatic system. Lymphocytes and other immune cells reside in them.

Lymphatic system Part of the circulatory system. One of its main functions is participating in the immune response.

Peptides Shorts chain of amino acids. They can be generated when proteins are digested into small pieces, peptides.

lesson 5.3 workbook - tufts university · b.bone marrow. c.thymus. ... after clonal expansion,...

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