W o r k b o o kLesson 5.3 1

The innate immune response will sound the alarm to prime the adaptive response.

As we began to discuss in the last lesson, innate immune cells and adaptive immune cells are very different. Innate immune cells inherit a limited number of receptors that recognize protein sequences that are highly con-served among pathogens (the protein sequences a receptor recognizes is called an antigen) . These receptors are limited but have a very important property - they can distinguish pathogens from self cells. If they can’t clear the infection they signal to adaptive immune cells to join the battle.

However, adaptive immune cells (B and T cells) are built very differently. There are billions of B and T cells in the body and each one of them has randomly made a single receptor. Between them there are receptors for billions of different targets - including antigens that may be found on any pathogen imaginable. But a single cell can’t provide the army needed to fight an infection by billions of pathogens, so they expand in number when an infection occurs. The role of the innate immune system is to tell the adaptive immune system which particular receptor-bearing cell it needs to expand in order to respond to a particular pathogen attack. It does this by presenting the right antigen to the adaptive cells and by stimulating them to divide with cytokines. Without this fail-safe step the adaptive immune system might expand its receptor bearing cells randomly - perhaps even rec-ognizing self cells (in fact this can occur in autoimmune diseases). But under normal circumstances only the specific B and T cells needed will expand to recognize the specific pathogen, and only when the innate immune system gives them permission to do so.

Evolving pathogens – our body’s re-sponses – B and T cells.

LESSON 5.3 WORKBOOKWhy might the innate responses not be able to control the infection?________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

What does the regulation of adaptive cells by innate cells prevent?________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

DEFINITIONS OF TERMS

Antigen: A part of a molecule that can be recognized by

a recpetor. It may be part of a protein, in which case it is sequence of between 5-15

amino acids, a sugar or a lipid.

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

This lesson transitions from innate immune responses to adaptive responses. It deals with the three main principles of adaptive immunity: One, each B and T cell can recog-nize only one ligand. Two, each B and T cell recognizes this ligand using a unique receptor that is produced ran-domly during development. Three, since each adaptive cell has a unique receptor it will need to divide in order to increase the number of cells that recognize that ligand before it will be able to successfully respond to the threat.

W o r k b o o kLesson 5.3 2

B and T cells are named according to the organs in which they are made

B cells are made in the bone marrow.

T cells are made in in the thymus.

Both B and T cells are called lympohcytes. But don’t be confused - in this context the word is simply being used as a synonym for ‘adaptive immune cell’.

The receptors on adaptive cells recognize antigens.Like innate immune cells, B and T cells use receptors to recognize pathogens. However, this recognition is very specific and the target is given a special name, antigen. As we saw on the previous page the definition of an antigen as ‘a part of a molecule that can be recognized by a receptor’ is a bit circular. For example, a B cell that recognizes the toxin made by Clostridium tetani has receptors that bind to the tetanus toxin, so tetanus toxin is called an antigen. Since adaptive receptors are so specific, a B cell that recognizes the tetanus toxin will not recognize anything else. We say that the B cell is antigen specific for tetanus toxin.The B cell receptor (BCR) can either be attached to the B cell membrane like a conventional receptor, or it can be secreted so that it is a soluble protein. In this case the it is called an antibody. We use the term BCR when the receptor is bound to a membrane, and the term antibody when the receptor is secreted, however it is still the same protein with the same antigen specificity. Like B cells, each T cell also expresses a unique T cell receptor (TCR). However, there are two main differences between B and T cell receptors: TCRs are never secreted like antibodies and TCRs ‘see’ antigens only when they are presented by an innate self-cell (the antigen-presenting cell).

DEFINITIONS OF TERMS

Antigen-specific: terminology that reflects the idea that one

receptor specifically recognizes one antigen.

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

LESSON MATERIALSWhat is an antigen?

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What is the difference between a BCR and an antibody?

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W o r k b o o kLesson 5.3 3

Individual B and T cells have numerous receptors but they are identical and unique for a specific antigen

Each B and T cell is covered with multiple identical receptors so they can only ‘see’ a single antigen. For this reason, a given B or T cell has antigen specificity. For example, a B cell may recognize a small sequence on the surface of the Strep. pneumoniae capsule. This structure is so precise it is not likely to be found anywhere else in nature. This is de-picted in the figure to the right, which shows that the B cell with the purple BCR binds the antigen, while the other B cells don’t. This is a lot like finger prints or DNA typing; the odds of finding two people with matching finger prints or DNA is very low. However, there are ex-ceptions and some antigens can be found on multiple pathogens, as we will see later this can be advantageous for vaccines.

B cells can only recognize extracellular antigens.

The BCR sits on the surface of a B cell waiting to bind to its antigen. This means that a BCR may bind to an antigen that is free floating (soluble), like a toxin, or to an antigen on the surface of a virus or bacteria. In the same way, the soluble receptors (antibodies) are also able to bind soluble or exposed antigens.

In fact, niether BCRs nor antibodies can cross the cell membrane, so they cannot ‘see’ intra-cellular antigens. Hence, they are not effective against intracellular pathogens unless they en-counter the pathogen on its way to infect new cells. For example, antibodies against the flu can prevent infection of epithelial cells but they cannot access the virus when it is in a host cell. Only T cells can to that!

LESSON MATERIALSB cell receptors and antibodies can only bind to antigen that is outside of a cell. How would the immune re-sponse ‘see’ an intracellular antigen?__________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

W o r k b o o kLesson 5.3 4

One cell with a antigen specific receptor is not enough to respond to an infection, so how do you make more? We have seen that the billions of receptors on the billions of B and T cells are made randomly so each type of cell has a unique receptor. This means that a person may have just one B and one T cell that recognizes tetanus toxin. But one cell is not enough to fight an infection or to neutralize a toxin. This means that we will need to increase the number of antigen specific B or T cells, in order to fight the infection specifically.But remember the receptors are made randomly when the B and T cells differentiate from stem cells, so simply differentiating more B and T cells may not produce any receptors specific to T cells, let alone enough cells to mount an immune response. What is the solution?

This slide shows that the B and T cells that recognize a specific antigen divide, while 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 is called clonal expansion because the division of activated B or T cells generates numerous cells that are identical, clones of the parent B and T cells. In this way, a B cell that recognizes ‘its’ antigen will expand rapidly to increase the number of B cells with that specific BCR. However this takes time, which accounts for the delay in the onset of the adaptive immune response. This delay is the ‘learning’ part of adaptive immunity. After the infection has been controlled some of the cells remain in case we are exposed to the same pathogen again, which is the memory part of adaptive immunity.

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LESSON MATERIALSWhy is clonal expansion needed for an effective adaptive immune response?________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________