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The specific response: selected, cloned, remembered

Your body carries millions of different lymphocytes, each able to recognise one shape and no other. An infection does not teach them anything; it finds the few that already fit and makes millions of copies. What is left afterwards is why the same pathogen rarely gets a second chance.

Before this Phagocytosis and antigen presentation · Protein tertiary structure and complementary shapes · Mitosis

Before you start

Memory cells are the ones that make antibody quickly the second time you meet a pathogen. Ask what one of them is doing in the twenty years between the two exposures, though, and the sentence comes apart: nothing. Memory cells secrete nothing at all while they circulate — they can survive for decades doing precisely that. What they do on re-exposure is divide, very fast, into plasma cells, and it is the plasma cells that secrete antibody. The speed of the secondary response comes from starting with thousands of the right cells instead of one.

What you should be able to do

Explain what an antigen is and how a lymphocyte distinguishes self from non-self.
Describe clonal selection and clonal expansion, and say which cell does which.
Set out the roles of T-helper cells, T-killer cells, B cells, plasma cells and memory cells without confusing any two of them.
Put the events from infection to circulating antibody into the right order.
Account for the secondary response being faster, larger and longer-lasting than the primary one.

Antigens, self and non-self

An antigen is a molecule the immune system can recognise — in practice a protein or glycoprotein sitting on a cell surface, where its shape is exposed. Proteins are used because there are effectively unlimited different shapes available, and shape is what recognition depends on.

Your own cells carry antigens too. During foetal development and shortly after birth, lymphocytes are produced with an enormous variety of receptor shapes, and any that happen to fit the antigens on your own cells either die or are suppressed. What survives is a population that responds to shapes your body does not contain. That is why the immune system tolerates you and attacks a transplanted kidney, and why autoimmune diseases such as type 1 diabetes and rheumatoid arthritis are described as a failure of that early screening rather than as an infection.

Antigen: A molecule, usually a surface protein or glycoprotein, that is recognised as self or non-self and can trigger an immune response.
Self: Antigens present on an organism's own cells, which its lymphocytes do not respond to.
Non-self: Antigens not present on the organism's own cells: pathogens, transplanted tissue, cancerous cells with altered surface proteins, and toxins.
Lymphocyte: A white blood cell carrying receptors of a single shape, produced in bone marrow; T cells mature in the thymus and B cells in the bone marrow.

The list of things counted as non-self is broader than 'germs'. A transplanted organ carries the donor's antigens, which is why recipients take immunosuppressants. Cancer cells often display abnormal surface proteins and are destroyed by the same mechanism, quietly and constantly. Toxins are foreign molecules in their own right and provoke antibodies against them without any cell being involved.

Selection, not instruction

The central idea of this topic is easy to state and easy to get backwards. Lymphocytes are not shaped by the infection. They exist already, in enormous variety, each with one receptor shape, and the infection simply picks out the ones that happen to fit.

Clonal selection: The binding of an antigen to the one lymphocyte whose receptor is complementary to it, activating that cell and no others.
Clonal expansion: The repeated division by mitosis of the selected lymphocyte, producing a large clone of genetically identical cells.

Selection is the meeting; expansion is the mitosis that follows. Losing the distinction is one of the commonest ways to lose marks here, and the wording that scores is usually 'the lymphocyte with the complementary receptor is selected, then divides by mitosis to form a clone'.

One presented antigen, one selected T-helper cell, and two responses that run at the same time. Follow the right-hand branch to find the only cell that secretes antibody.

Notice where the flow starts. Not with the pathogen, and not with a B cell — with a phagocyte that has already destroyed a pathogen and put its antigens on display. That is the link back to the previous lesson, and questions that ask you to describe the immune response from the beginning expect it as the first step.

The cellular response

T lymphocytes are made in the bone marrow and mature in the thymus. Each carries receptors of one shape, and — this is the part that distinguishes the cellular response — a T cell responds to antigen presented on a cell surface, not to free antigen floating in plasma.

A T-helper cell whose receptor is complementary to the presented antigen binds to the antigen-presenting cell. That is clonal selection. The bound cell is activated and divides rapidly by mitosis, producing a clone of active T-helper cells together with memory T cells that persist. What that clone then does is the part worth writing down, because all of it is stimulation of somebody else. Activated T-helper cells stimulate phagocytes to engulf more actively; they activate the B cells that will go on to secrete antibody; and they activate T-killer cells.

Watch that verb, because it is the one the mark scheme uses. A T-helper cell does not turn into a T-killer cell and never could. The two are separate lineages, committed while they were still maturing in the thymus: a helper carries CD4 and answers to antigen presented by another cell, a killer carries CD8 and goes looking for infected cells to destroy. Neither becomes the other any more than a neurone becomes a red blood cell. Write 'differentiates into T-killer cells' and you have described a change that does not happen; write 'activates T-killer cells' and you have the mark.

T-killer cells — cytotoxic T cells — deal with host cells that are already infected. A cell containing a replicating virus displays viral antigens on its own surface, and a T-killer cell with the complementary receptor binds to it and releases perforin, a protein that makes pores in the cell-surface membrane. The membrane is no longer a barrier, substances move freely in and out, and the cell dies before the virus inside it can finish replicating. It is a controlled loss: one of your own cells is sacrificed because it has already been taken over.

Nothing in the cellular response produces antibody. If a question asks for the role of T cells and you write 'they make antibodies', that is a straightforward error rather than an imprecision.

The importance of the T-helper cell is easiest to see in what happens when it is lost. HIV infects T-helper cells specifically, using the CD4 protein on their surface as its way in, and replicates inside them. Over years, untreated, the number of T-helper cells falls far enough that B cells are no longer activated properly and T-killer cells are no longer stimulated. The specific response stops working, and the infections that follow — pneumonia, tuberculosis, certain cancers — are what constitute AIDS. The patient does not die of HIV; they die of something an intact immune system would have handled.

The humoral response

B lymphocytes mature in the bone marrow, and each one carries thousands of copies of a single antibody embedded in its cell-surface membrane, acting as its receptor. Between them, the B cells in your body carry something of the order of ten million different antibody shapes, none of which was designed for any particular pathogen.

When an antigen with a complementary shape binds to a B cell's surface antibody, the B cell takes it in, processes it, and presents it on its own surface. An activated T-helper cell with the matching receptor binds there and stimulates the B cell to divide. This is clonal selection again, applied to a different cell, and it is why the two responses cannot be separated: without T-helper cells, most B cells are never properly activated.

The clone that results differentiates into two kinds of cell, and the difference between them is the whole of the next section.

Plasma cell: A differentiated B cell that secretes large quantities of a single antibody into blood and lymph, and survives only a few days.
Memory cell: A long-lived cell produced by clonal expansion that does not secrete antibody, but divides rapidly into plasma cells if the same antigen is met again.

A plasma cell is a factory with a short lease. It secretes on the order of two thousand antibody molecules a second and lives for a few days — which is why antibody concentration in the blood falls away once an infection is cleared. Memory cells do the opposite: they secrete nothing, and some survive for decades. Immunity to measles after infection is usually lifelong, and it is lifelong because of cells doing nothing in particular for forty years.

Cell	Where it acts	What it does	How long it lasts
T-helper	On antigen-presenting cells	Activates B cells, T-killer cells and phagocytes	Days; memory forms
T-killer	On infected body cells	Releases perforin, so the infected cell dies	Days
B cell	In lymph nodes and blood	Selected by antigen, then clones itself	Days
Plasma cell	Blood and lymph	Secretes antibody continuously	A few days
Memory cell	Blood and lymph	Secretes nothing; divides fast on re-exposure	Years to decades

Why the second time is different

Put the two responses on the same axes and the difference is obvious, provided the vertical axis is logarithmic — on a linear scale the primary response is barely visible at all.

Three differences to read off, not one: the secondary response starts sooner, rises far higher, and is still going when the primary response had already disappeared.

The primary response is slow because almost everything has to happen from scratch. A phagocyte must present the antigen; the handful of lymphocytes with a complementary receptor must be found among millions; those cells must divide repeatedly before there are enough of them to matter; and only then do plasma cells appear. Eight days or so is typical before there is measurable antibody, and the person is ill for most of it.

The secondary response starts from a completely different position. Memory cells specific to that antigen are already circulating, in thousands rather than ones, and they are already committed — they divide straight into plasma cells without waiting to be selected out of a crowd. Antibody appears within two or three days, reaches a concentration perhaps a hundred times higher, and stays high for longer because more memory cells are made in the process. The pathogen is usually destroyed before it has reproduced enough to cause symptoms, which is what people mean when they say they are immune.

Reading the graph as an examiner would

Using the graph, describe two differences between the primary and secondary responses, and explain the difference in the time taken for antibody to become detectable.

Describe with figures. Antibody becomes detectable about eight days after the first exposure and about two days after the second; the peak concentration is roughly a hundred times higher after the second exposure. Quoting numbers off the axes is what 'using the graph' asks for.

Explain with cells. After the first exposure, the antigen had to be presented, a single B lymphocyte with a complementary antibody had to be selected, and clonal expansion had to run for several generations before plasma cells existed in useful numbers.

After the second exposure, memory cells specific to that antigen were already present in large numbers. Clonal selection had already happened, so those cells divided rapidly and differentiated into plasma cells almost at once, and far more plasma cells were produced.

Watch the axis. Each gridline is a tenfold increase, so a peak two gridlines higher is a hundred times more antibody, not twice as much. The scale is logarithmic for a reason: drawn linearly, the primary response would be a flat line along the bottom of the page and there would be nothing to compare.

Getting the order right

Sequencing questions are common in this topic and they are marked strictly. The order, from a pathogen entering the body to antibody in the plasma, is this:

The pathogen enters and is engulfed by a phagocyte, which hydrolyses it and presents its antigens on its own cell-surface membrane. A T-helper cell with a complementary receptor binds to the presented antigen and is activated — clonal selection — and divides by mitosis. Meanwhile the same antigen binds to the surface antibody of the B cell that fits it, and the B cell processes and presents it. An activated T-helper cell binds to that B cell and stimulates it. The B cell divides by mitosis, clonal expansion, and the clone differentiates into plasma cells, which secrete antibody, and memory cells, which do not.

Two errors dominate. The first is starting with the B cell, which skips the phagocyte entirely and loses the first mark. The second is having memory cells secrete antibody; they divide into plasma cells, and the plasma cells secrete.

TRY IT — Same pathogen, different patient

A patient receiving immunosuppressant drugs after a kidney transplant develops a bacterial infection. Their phagocytes are unaffected by the drugs, but their T-helper cells are greatly reduced in number. Predict how their antibody response to the infection will differ from a healthy person's, and explain why.

Check your answer

Phagocytosis will be normal. It is non-specific, needs no lymphocytes, and antigen will still be presented on the phagocytes' surfaces.

The antibody response will be much smaller and much slower. B cells can bind antigen with their surface antibody, but most of them are not fully activated until an activated T-helper cell with a complementary receptor binds to the antigen they are presenting. With few T-helper cells, that second signal rarely arrives.

So clonal expansion of B cells is limited, few plasma cells are produced, and antibody concentration stays low. Fewer memory cells are made as well, so a later exposure to the same bacterium will not produce a proper secondary response either.

This is the same reasoning that explains untreated HIV infection. The difference is the cause — a drug taken deliberately in one case, a virus that infects T-helper cells in the other — and the consequence is much the same.

In the exam

'Clonal selection' and 'clonal expansion' are two different marks. Selection is the antigen binding the one lymphocyte with a complementary receptor; expansion is that cell dividing by mitosis. Write both.
Say complementary, not 'the same shape'. A receptor and an antigen fit together; they are not identical.
Plasma cells secrete antibody. Memory cells do not, until they have divided into plasma cells. Any answer that has memory cells secreting will lose the mark however good the rest of it is.
HIV infects T-helper cells. AIDS is the condition that follows when enough of them are destroyed. Using the two words interchangeably reads as not knowing the difference, because usually it is.
On a logarithmic axis, count gridlines. Two decades is a hundredfold, and questions that supply a log scale nearly always want a fold-change quoted.
Sequencing questions start with the phagocyte, not the B cell. If you are unsure how much detail to give, give the order first and the detail second.

Check yourself

A vaccine against a bacterium is given to a child, who develops a mild fever for a day and no other symptoms. Eighteen months later the child is exposed to the live bacterium and does not become ill at all. Explain what happened on each occasion, in terms of the cells involved.

Answer

The vaccine contained antigens from the bacterium. Phagocytes engulfed them and presented the antigens on their cell-surface membranes, and a T-helper cell with a complementary receptor was selected and divided by mitosis.

B cells whose surface antibody was complementary to the same antigen took it in and presented it, were stimulated by activated T-helper cells, and underwent clonal expansion. The clone differentiated into plasma cells, which secreted antibody over the following days, and memory cells, which remained. This was a primary response: slow, small and, because there was no live pathogen reproducing, symptom-free apart from the fever produced by the response itself.

Eighteen months later the memory cells were still circulating. On exposure, the same antigen bound to memory B cells that were already present in large numbers and already selected, so they divided rapidly into plasma cells. Antibody appeared within two or three days rather than eight, at a much higher concentration.

The bacteria were agglutinated and marked for phagocytosis before they had reproduced enough to cause symptoms. The child was never ill because the response was faster than the infection, not because the bacteria never entered.

Questions

Written to the command words the boards use. Try them on paper before opening a scheme: the marks go to points made, not to length.

Question 15 marks

Describe the sequence of events from a pathogen entering the body to antibody appearing in the blood plasma.

Mark scheme

B1 the pathogen is engulfed by a phagocyte, which hydrolyses it and presents its antigens on its own cell-surface membrane
B1 a T-helper cell with a complementary receptor binds to the presented antigen and is activated, which is clonal selection, and divides by mitosis
B1 the same antigen binds to the surface antibody of the B cell that fits it, and that B cell takes the antigen in, processes it and presents it
B1 an activated T-helper cell binds to the presenting B cell and stimulates it to divide by mitosis, which is clonal expansion
B1 the clone differentiates into plasma cells, which secrete antibody, and memory cells, which secrete nothing

Question 24 marks

Explain why detectable antibody appears about eight days after a first exposure to an antigen but only about two days after a second exposure to the same antigen.

Mark scheme

B1 on the first exposure the antigen must first be presented by a phagocyte, and the few lymphocytes with a complementary receptor must be selected out of millions
B1 those selected cells must then divide repeatedly by mitosis before enough exist to matter, and only then do plasma cells appear and begin secreting
B1 on the second exposure, memory cells specific to that antigen are already circulating in thousands rather than ones, so selection has already happened
B1 the memory cells divide rapidly straight into plasma cells, so antibody is secreted in quantity within about two days

Question 34 marks

Explain why an untreated HIV infection eventually leaves a person unable to deal with infections that an intact immune system would handle easily.

Mark scheme

B1 HIV infects T-helper cells specifically, using the CD4 protein on their surface as its way in, and replicates inside them
B1 the infected cells are destroyed as new virus particles are released, so over years the number of T-helper cells falls
B1 B cells are no longer properly activated, so few plasma cells are produced and little antibody is secreted
B1 T-killer cells are no longer activated, so infected body cells are not destroyed; the infections that follow are what constitute AIDS

Question 44 marks

A virus is replicating inside the cells lining a person's airways. Suggest how T-killer cells limit the infection, and suggest why antibody alone would not be enough.

Mark scheme

B1 a cell containing a replicating virus displays viral antigens on its own cell-surface membrane
B1 a T-killer cell with a complementary receptor binds to that cell and releases perforin, which makes pores in the cell-surface membrane
B1 the membrane is no longer a barrier, substances move freely in and out, and the infected cell dies before the virus inside it can finish replicating
B1 antibody binds antigens outside cells, so it cannot reach virus particles already inside a host cell; only destroying the infected cell removes them

Question 52 marks

State what is meant by clonal selection and state what is meant by clonal expansion.

Mark scheme

B1 clonal selection is the binding of an antigen to the one lymphocyte whose receptor is complementary to it, activating that cell and no others
B1 clonal expansion is the repeated division of that selected lymphocyte by mitosis, producing a large clone of genetically identical cells

Worth remembering

Lymphocytes are selected by an antigen, not instructed by it: the shapes exist before the infection does.
Clonal selection is the binding; clonal expansion is the mitosis that follows.
T cells respond to antigen presented on a cell surface; B cells can bind free antigen, but still need a T-helper cell to be fully activated.
Plasma cells secrete antibody for days. Memory cells secrete nothing for years, then divide into plasma cells.
The secondary response is faster, larger and longer-lasting because it starts with thousands of the right cells instead of one.

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