Neurobiology 104 Reading
for the next three lectures
October 20, 2003 G&H
Chap. 12 plus pp 231-233
LYMPHOCYTES
Most kinds of cells belong to discrete "cell
types" in which all cells
are equivalent.
In contrast, lymphocytes are extraordinarily
heterogeneous.
Various types of cells that interact with lymphocytes
also are diverse, including reticular cells,
dendritic cells, and
endothelial cells.
A variety of quite different cell types assume the
form of "small
lymphocytes" when they are inactive. The small lymphocyte is a
resting
stage for cells circulating in blood or wandering in C.T.
4 major classes of lymphocytes are B, T, NK and stem
cells.
Each of
these classes is heterogeneous.
Classes and subclasses are hard to distinguish
morphologically.
-> Their most diagnostic features are the
proteins on the cells'
surfaces,
called cell differentiation (CD) proteins.
Classes are developmentally distinct: e.g. consider B
and T cells.
In birds,
pre-T and pre-B cells originate in red bone marrow and
migrate to separate organs to mature:
Pre-T
cells go to the thymus. Pre-B cells to
the bursa.
Removing either organ at birth abolishes that class of cells.
Mammals
have a thymus for T cells but no bursa.
Pre-B
cells probably mature in the bone marrow.
Lymphocytes do vary in appearance but mainly due to
differences in their
states of commitment to divide.
lymphoblasts --> prolymphocytes --> small lymphocytes
Lymphoblasts ("large lymphocytes") have
large pale nuclei and
substantial amounts of faintly basophilic cytoplasm.
They
can actively divide.
Small lymphocytes cannot divide as such.
They
first must dedifferentiate into lymphoblasts.
Prolymphocytes ("medium-sized lymphocytes")
are intermediates.
WARNING: The "large" lymphocytes of blood
are not lymphoblasts.
Lymphoblasts and prolymphocytes do not circulate in blood.
Cells can cycle repeatedly between blast and small
lymphocyte forms.
A possible killer T cell
lineage:
Stage Morphological
form Location
Blast Yolk sac
/
Stem cell SL
\ Bone marrow
Blast
/
Pre T cell SL Blood
|
Thymic
lymphocyte SL = Blast Thymus
|
Killer
type T cell SL
\
Stimulated killer Blast
/
Memory killer
SL Peripheral
C.T.
\
2nd
response killer Blast
(SL=small lymphocyte, Blast=lymphoblast)
B
cells
B cells
can be induced to mature into plasma cells.
which
then secrete massive quantities of antibodies.
Antibodies are proteins with binding sites for antigen molecules.
See G&H Fig. 12-1
A person
can make any of 10,000,000 or so types of antibody
molecules, each with a different amino acid sequence.
--> Problem
#1: How do genes encode this repertoire of information?
Crucial fact: Each B cell can make only
a single type of antibody.
Antibody diversity comes from diversity among B cells.
A
variety of genetic mechanisms generate the enormous
diversity among antibodies.
a. Antibody proteins are encoded by multigene families.
b. The two polypeptide chains of antibodies, L and H,
can associate in different combinations.
c. Antibody genes are split into several segments and
each segment is tandemly repeated.
During development
one randomly chosen member of each segment is spliced
together to form a complete L gene and an H gene.
d. The exact point of gene splicing is variable.
e. Extra nucleotides are inserted at junctional
sites into the DNA helix in a non-templated manner.
f. Point mutations are introduced into the completed
L and H genes to produce somatic cell variants.
g. Other mechanisms:
Premessenger RNA's can be differentially spliced.
Birds use gene conversion with pseudogenes.
B cells differ
in their genetic (DNA) sequence from other cell types.
--> Problem
#2: How do antigens induce only appropriate antibodies?
(ones which will bind to those particular antigens)
The clonal selection theory proposes a
2-step process.
1. During its
formation each B cell generates a unique L and H gene,
thus
irreversibly committing the cell to a particular antibody
specificity before encountering any antigen.
It
synthesizes a small number of antibody molecules and attaches
them
to its cell surface as a receptor to detect that antigen.
A trillion
lymphocytes wander through a person's blood, lymph and
connective tissues looking for antigens. These include cells
committed to millions of antigens which the person has
not
yet, and in most cases never will, encounter.
2. When antigen binds to its receptors, a B cell
reverts to a
blast
form and divides into a clone of identical cells.
B
cell ----> immunoblast -----> plasma cell
memory B cell
Some
progeny cells differentiate into plasma
cells.
(factories for secreting antibody).
Others
differentiate back to small lymphocytes as memory
cells
These are easier to reactivate to immunoblasts than
before,
and allow a person to respond more rapidly and vigorously
when re-exposed to an antigen (i.e. "booster"
response or
"amnestic response").
3. A mutation mechanism generates further variation
when activated
lymphocytes
are stimulated to divide.
The
mutant cells compete for available antigen.
Those with the
most
avid antibody out reproduce the others.
Thus, the ongoing
immune
response "evolves" towards better and better antibodies.
T
CELLS
T cells resemble B cells but are more diverse and
complex in function.
1. They make a "T cell receptor" protein
instead of antibody.
It: -
is homologous to the antibody molecule.
- forms through gene
rearrangement.
- varies in binding specificity
from one T cell to another.
But it:
- is always bound to the cell membrane.
- binds only to antigen which
has been digested into small
peptides that are held on the surface of other cells
by a
"major histocompatibility (MHC) protein.
2. Subtypes of T cells carry out different functions.
Cytotoxic T
cells provide "cellular immunity" distinct from the
"humoral immunity" from B cells and antibody.
Rejection
of a graft of foreign tissue is an example.
T cells
migrate into the graft, divide, become activated
as
killer T cells and kill the cells of the graft.
1. by
punching holes in the cell membrane.
They secrete proteins which go into the membrane of
target cells and assemble into pores.
2. by
inducing the target cell to commit suicide.
i.e. they induce the pathway for apoptosis.
The main function of cytotoxic T cells is to kill
cells that are infected by viruses.
Helper T
cells help to activate B cells.
In
general, B cells cannot be activated by antigen unless aided
by
helper T cells which also have been activated.
T cells
also regulate the activation of other T cells.
Some T
cells may regulate formation of other blood cell types:
eosinophils, mast cells and maybe red blood cells.
Suppresser T
cells inhibit the activation of B cells.
They are
important for self tolerance.
A
variety of complex mechanisms prevent a person from
making antibodies to his own proteins.
Suppresser T cells can be distinguished from helpers by the
CD
proteins on their cell surfaces (i.e. CD8 vs CD4).
3. T cells secrete chemical messengers called
interleukins as another
part of
their functions.
See G&H
Table 12-3
4. T cells develop from a complex clonal selection
process;
Pre T cells
rearrange their T cell receptor gene in the thymus.
An
extra winnowing step in the thymus removes newly formed
T
cells that would react to "self" proteins.
Cells with
acceptable receptors leave the thymus as mature T cells.
5. T cells can be activated only by interacting with antigen presenting
cells (APC's).
These cells:
-
phagocytize extracellular proteins, digest them, place peptide
fragments on Class II MHC molecules and "present" them on
their cell surface to T cells.
-
activate T cells whose T cell receptors recognize those
peptides, using a combination of direct cell-cell contact and
secretion of chemical messengers.
See G&H fig. 12-3
Antigen presenting cells include dendritic cells,
lymphocytes, and macrophages.
T cells
also can turn other cells into auxiliary APC's
by
secreting gamma interferon (e.g. endothelial cells).
Most
other cell types of the body also present peptides, but in a
different
way. They digest samples of their own
proteins and
place
fragments on Class I MHC molecules.
Evolutionary considerations:
1. B cells
probably evolved from a subfamily of T cells.
2. MHC
proteins are homologous to antibody molecules.
A large number of other proteins with functions in
immunity are homologous in structure to antibodies.
This immunoglobulin
superfamily probably evolved by repeated
gene
duplication and divergence as the immune system became
more
elaborate.
NATURAL KILLER CELLS
Natural killer cells (NK) survey the body for tumor
cells. They:
-
correspond to those "large lymphocytes" in blood with
scattered granules.
- may
actually be relatives of macrophages
- do not
requiring prior induction.
There appear to be two or more sorts of NK cells.
STEM CELLS
The pluripotential stem cells of bone marrow:
- can
develop into any of the blood cell types.
- look like
lymphocytes when they are inactive.
- must
revert to blast forms to divide.
The
presumed blast form of pluripotential stem cells is
called a "Hemocytoblast".
It
occurs in bone marrow and in blood.
- can
differentiate into progenitors of individual cell lineages.
- can
circulate in blood as lymphocytes (blast cells do not).
A progenitor cell
- can give rise to a single cell type.
- is usually denoted CFU (colony forming
unit), eg CFU-E, CFU-M
- can assume the form of lymphocytes at
various early stages of
differentiation into its final cell type.
eg
three early stages in the erythrocyte lineage are
represented by different lymphocyte forms;
CFU-s -> BFU-E -> CFU-E
Hemopoietic Progenitor and stem cells:
- are
difficult to study histologically because they are rare and
they all
look alike in their blast and resting forms.
- were
identified in cell culture, from the cells they produce when
activated to divide and differentiate.
- can be
recognized by proteins on their cell surfaces.
- are
activated by secreted proteins called CSF's
(colony
stimulating factors) or poietins (see table 10-6).
Other minor classes of lymphocytes probably await
discovery.
For
example, mast cells and dendritic cells originate in bone
marrow and
migrate through the blood to their final location,
probably
in the form of small lymphocytes.
There
are at least two subtypes of mast cells and
dendritic cells are considerably more heterogeneous.