Transcript Sept15_lecture8a_immunology

Lecture 8
Immunology and disease: how
vertebrate immunity works
Today
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Lymphocytes
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How does the “right” lymphocyte arise?
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Lymphocyte receptor diversity
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Clonal selection
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Different types of T-cells
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Architecture of immunity
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Origins of adaptive immunity (next time)
Lymphocytes
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
Lymphocytes
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The phenomena of antibody formation, immunological
memory, and the success of vaccines were well known
before 1900
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It wasn’t until the 1950s that it became clear that they were
all due to lymphocytes
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Lymphocytes make up about a third of the white blood cells
and are very different from other leukocytes like phagocytes
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They are very long lived (years/decades)
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They recirculate from blood to tissues and back again
Lymphocytes
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Each endlessly searches for its unique target
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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
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(Think Holmes and Moriarty)
Lymphocytes
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To increase the chance of “seeing” its nemesis, there are
special locations where pathogens and lymphocytes are
likely to meet
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These are the lymphoid organs, most importantly the lymph
nodes (or glands)
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When you have swollen glands, say in your throat, there’s a
lot going on…
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Lymphocytes recognizing the invading virus or bacteria
home in to do battle
Lymphocytes
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Unless it takes extraordinary precautions, a pathogen cannot
avoid coming into contact with the “right” lymphocyte sooner
or later
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That marks the beginning of the end for most invaders
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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” lymphocyte
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By “right” we’re talking about receptors
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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)
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Slipper = receptor
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Foot = some tiny portion of the pathogen (epitope)
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Sort of similar to phagocytes, but with a crucial difference
What?
Phagocyte
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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
Lymphocytes
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Each lymphocyte carries
thousands of copies of a
single receptor
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It can recognize only one
single shape, unique to that
lymphocyte
The “right” lymphocyte
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Paul Ehrlich (1854-1915)
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Put forward the fundamental immunological idea of unique
receptors on cells in 1890!
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70 years before it was confirmed
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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” lymphocyte
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The lymphocyte type of recognition is often referred to as
specificity (“specific” immunity and so on)
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To refer to the phagocyte type of innate immunity as “nonspecific” is a bit unfair since they can distinguish perfectly
well between most pathogens and normal body cells
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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
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It is shape-directed: millions of shapes, millions of receptors
So, where does the diversity come from?
Lymphocyte receptor diversity
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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
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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 diversity
2. Each chain is built of multiple segments that are combined
by specially controlled recombination (somatic
recombination)
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Heavy chains have three regions that affect recognition
(receptor binding), variable (V), diversity (D), and joining
(J)
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Light chains have only V and J regions
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In humans there are about 100 different V genes, 12 D
genes, and 4 J genes
Lymphocyte receptor diversity
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Each progenitor of a B-cell clone undergoes somatic
recombination that brings together a V-D-J combination for
the heavy chain
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There are 100X12X4 = 4,800 V-D-J combinations
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Similar recombination events lead to the light chain
How many possible light chain combinations are there?
And heavy plus light chain combinations?
Lymphocyte receptor diversity
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4,800 V-D-J combinations for the heavy chain
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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 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
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The V-D-J shuffle will be different for each lymphocyte, and
is then locked in for that lymphocyte
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The glass slipper doesn’t change…much. But it changes a
bit through somatic hypermutation (Haldane’s idea)
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Somatic recombination gives a combinatorial pool of
diversity which is then fine tuned
Lymphocyte receptor diversity
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Upon infection, one of the clones generated by VDJ
recombination of might fit a pathogen epitope like
Cinderella’s slipper
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This stimulates amplification of that clone
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The new generation of clones increase their mutation rate at
recognition site
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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 diversity
Clonal selection
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The process that underlies lymphocyte specificity and
differentiation is akin to natural selection
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only those lymphocytes that encounter an antigen to which
their receptor binds will be activated to proliferate and
differentiate into effector cells
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This selective mechanisms was first proposed in the 1950s
by the Australian biologist Frank MacFarlane Burnet…
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…at a time when nothing was known about lymphocyte
receptors, or even that lymphocytes were important
Clonal selection
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It wasn’t until the 1960s that James Gowans removed
lymphocytes from rats and noticed that their adaptive
immunity disappeared
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Peter Medawar removed the last conceptual problem in the
1950s by showing how the problem of immune responses to
“self” is solved
How?
Clonal selection
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Exposure to foreign tissues during embryonic development
of mice caused them to become tolerent of those tissues
later (I.e. no immune response)
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Led to the idea that developing lymphocytes that are
potentially self-reactive are removed before they can mature
= clonal deletion
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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 selection
The proliferation of lymphocytes after clonal
selection leads to immunological memory
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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
diversity generation
The proliferation of lymphocytes after clonal
selection leads to immunological memory (and
vaccines)
Types of lymphocytes
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B-cells produce immunoglobulins, molecules produced by
adaptive immunity to dispose of particular threats
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Antibody = immunoglobulin = free-floating B-cell receptor.
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B-cells’ main job is to produce humoral immunity, to
neutralize pathogens floating anywhere outside of cells
(extracellular)
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That’s enough about them