Lecture 8 Immunology and disease: how vertebrate immunity works.

Lecture 8

Immunology and disease: how vertebrate immunity works

TodayToday

• Lymphocytes

• How does the “right” lymphocyte arise?

• Lymphocyte receptor diversity

• Clonal selection

• Different types of T-cells

• Architecture of immunity

• Origins of adaptive immunity (next time)

LymphocytesLymphocytes

Lymphocytes, like wasps, are genetically programmed for exploration, but each of them seems to be permitted a different, solitary idea. They roam through the tissues, sensing and monitoring. Since there are so many of them, they can make collective guesses at almost anything antigenic on the surface of the earth, but they must do their work one notion at a time. They carry specific information in the surface receptors, presented in the form of a question: is there, anywhere out there, my particular molecular configuration?

Lewis Thomas, 1974

LymphocytesLymphocytes

• The phenomena of antibody formation, immunological memory, and the success of vaccines were well known before 1900

• It wasn’t until the 1950s that it became clear that they were all due to lymphocytes

• Lymphocytes make up about a third of the white blood cells and are very different from other leukocytes like phagocytes

• They are very long lived (years/decades)

• They recirculate from blood to tissues and back again

LymphocytesLymphocytes

• Each endlessly searches for its unique target

• When a new pathogen appears somewhere in the body, only one or a few out of the millions and millions of lymphocytes will be able to recognize it

• (Think Holmes and Moriarty)

LymphocytesLymphocytes

• To increase the chance of “seeing” its nemesis, there are special locations where pathogens and lymphocytes are likely to meet

• These are the lymphoid organs, most importantly the lymph nodes (or glands)

• When you have swollen glands, say in your throat, there’s a lot going on…

• Lymphocytes recognizing the invading virus or bacteria home in to do battle

LymphocytesLymphocytes

• Unless it takes extraordinary precautions, a pathogen cannot avoid coming into contact with the “right” lymphocyte sooner or later

• That marks the beginning of the end for most invaders

• At this point, via antibody production (B-cells) and/or various killing devices mediated (T-cells), the lymphocytes wage all out war on the pathogen

What is meant by the “right” lymphocyte?

How does a lymphocyte get to be “right”?

How many sorts of lymphocyte are there?

The “right” lymphocyteThe “right” lymphocyte

• By “right” we’re talking about receptors

• Protein molecules on the surface of the lymphocytes that can bind tightly to suitably shapes molecules (think lock/key or cinderella’s slipper and foot)

• Slipper = receptor

• Foot = some tiny portion of the pathogen (epitope)

• Sort of similar to phagocytes, but with a crucial difference

What?

• The cells of innate immunity (like phagocytes) carry many different types of receptor

• All phagocytes carry the same set of 15 or more receptors of PAMPs

Phagocyte Lymphocytes

• Each lymphocyte carries thousands of copies of a single receptor

• It can recognize only one single shape, unique to that lymphocyte

The “right” lymphocyteThe “right” lymphocyte

• Paul Ehrlich (1854-1915)

• Put forward the fundamental immunological idea of unique receptors on cells in 1890!

• 70 years before it was confirmed

• He thought the bonds would be chemical but they turned out to be physical--just like a slipper and foot.

“The indefatigable industry shown by Ehrlich throughout his life, his kindness and modesty, his lifelong habit of eating little and smoking incessantly 25 strong cigars a day, a box of which he frequently carried under one arm…have been vividly described.”

The “right” lymphocyteThe “right” lymphocyte

• The lymphocyte type of recognition is often referred to as specificity (“specific” immunity and so on)

• To refer to the phagocyte type of innate immunity as “non-specific” is a bit unfair since they can distinguish perfectly well between most pathogens and normal body cells

• That’s actually more than lymphocytes can do: they have no way of knowing if the shape they bind to is part of a pathogen, a harmless symbiont, or one of the body’s own cells

• It is shape-directed: millions of shapes, millions of receptors

So, where does the diversity come from?

Lymphocyte receptor diversityLymphocyte receptor diversity

• Humans have about 30,000 genes, so there’s clearly not one gene for each of the tens of millions of different receptors on our T-cells

• Instead we have a combination of three things:

1. Receptors (at least B-cell ones) are composed of two protein chains, each different

Lymphocyte receptor diversityLymphocyte receptor diversity

2. Each chain is built of multiple segments that are combined by specially controlled recombination (somatic recombination)

• Heavy chains have three regions that affect recognition (receptor binding), variable (V), diversity (D), and joining (J)

• Light chains have only V and J regions

• In humans there are about 100 different V genes, 12 D genes, and 4 J genes

Lymphocyte receptor diversityLymphocyte receptor diversity

• Each progenitor of a B-cell clone undergoes somatic recombination that brings together a V-D-J combination for the heavy chain

• There are 100X12X4 = 4,800 V-D-J combinations

• Similar recombination events lead to the light chain

How many possible light chain combinations are there?

And heavy plus light chain combinations?

Lymphocyte receptor diversityLymphocyte receptor diversity

• 4,800 V-D-J combinations for the heavy chain

• 400 V-J combination for the light chain

= 1,920,000 different B-cell receptors (aka immunoglobulins, aka antibodies)

Plus there are random DNA bases added between segments, so the possible diversity is pretty much infinite

There are lymphocytes with around 100 million specificities floating around inside each of us…

Lymphocyte receptor diversityLymphocyte receptor diversity

3. Finally, the six areas of the genes that code for the parts of the receptor that do the recognizing can undergo further small changes due to mutations within individual lymphocytes

• The V-D-J shuffle will be different for each lymphocyte, and is then locked in for that lymphocyte

• The glass slipper doesn’t change…much. But it changes a bit through somatic hypermutation (Haldane’s idea)

• Somatic recombination gives a combinatorial pool of diversity which is then fine tuned

Lymphocyte receptor diversityLymphocyte receptor diversity

• Upon infection, one of the clones generated by VDJ recombination of might fit a pathogen epitope like Cinderella’s slipper

• This stimulates amplification of that clone

• The new generation of clones increase their mutation rate at recognition site

• This creates slight variation in the clone population, and variants with tighter binding are stimulated to divide more rapidly = affinity maturation

Remind you of anything?

Lymphocyte receptor diversityLymphocyte receptor diversity

Clonal selectionClonal selection

• The process that underlies lymphocyte specificity and differentiation is akin to natural selection

• only those lymphocytes that encounter an antigen to which their receptor binds will be activated to proliferate and differentiate into effector cells

• This selective mechanisms was first proposed in the 1950s by the Australian biologist Frank MacFarlane Burnet…

• …at a time when nothing was known about lymphocyte receptors, or even that lymphocytes were important

Clonal selectionClonal selection

• It wasn’t until the 1960s that James Gowans removed lymphocytes from rats and noticed that their adaptive immunity disappeared

• Peter Medawar removed the last conceptual problem in the 1950s by showing how the problem of immune responses to “self” is solved

How?

Clonal selectionClonal selection

• Exposure to foreign tissues during embryonic development of mice caused them to become tolerent of those tissues later (I.e. no immune response)

• Led to the idea that developing lymphocytes that are potentially self-reactive are removed before they can mature = clonal deletion

• these sorts of experiments are why we call MHC MHC(major histocompatibility complex)

Figure 1-15

Figure 1-14 part 1 of 2

Figure 1-14 part 2 of 2

Clonal selectionClonal selection

The proliferation of lymphocytes after clonal selection leads to immunological memory

• After a lymphocyte is activated, it takes 4-5 days of proliferation before clonal expansion is complete

• That’s why adaptive responses occur only after a delay of several days

• After this primary response, some antigen-specific cells persist and lead to a more rapid and effective secondary response, and lasting immunity = immunological memory

Clonal selection, adaptive immunity, and Clonal selection, adaptive immunity, and diversity generationdiversity generation

The proliferation of lymphocytes after clonal selection leads to immunological memory (and vaccines)

Types of lymphocytesTypes of lymphocytes

• B-cells produce immunoglobulins, molecules produced by adaptive immunity to dispose of particular threats

• Antibody = immunoglobulin = free-floating B-cell receptor.

• B-cells’ main job is to produce humoral immunity, to neutralize pathogens floating anywhere outside of cells (extracellular)

• That’s enough about them