Lymphocytes
As befits the cell of adaptive immunity, the
lymphocyte has several unique
features: restricted receptors permitting each cell to respond to an individual
antigen (the basis of specificity), clonal proliferation and long
lifespan (the basis of memory), and recirculation from the tissues back
into the bloodstream, which ensures that specific memory following a local
response has a body-wide distribution.
The discovery in the early 1960s of
the two major lymphocyte sub-populations, T (thymus-dependent; top) and
B (bursa or bone marrow- dependent;
bottom), had roughly
the same impact
on cellular immunology as the
double helix on molecular biology. The first property of T cells to be
distinguished was that of ‘helping’ B cells to make antibody, but further
subdivisions have subsequently come to light, based on both functional and
physical differences (top right). In the figure, the main surface features (or
‘markers’) of the various stages of lymphocyte differentiation are given, using
mainly the CD classification (see Appendix III) but also indicating the
production of key cytokines. Cells resembling lymphocytes, but without
characteristic T-cell or
B-cell markers, are referred to as
‘null’. This group probably includes early T cells, B cells and ‘natural killer’ cells important in tumour
and virus immunity. In blood and
lymphoid organs, up to 10% of lymphocytes are ‘null’.
One of the most exciting
developments in biology was the discovery that it is possible to perpetuate
individual lymphocytes by fusing them with a tumour cell. In the case of B
lymphocytes, this can mean an endless supply of individual, or monoclonal,
antibodies, which has had far-reaching applications in the diagnosis and
treatment of disease and the study of cell surfaces. Indeed, the classification
of lymphocytes themselves, and of most other cells too, is now mainly based on
pat- terns of reactivity with a large range of monoclonal typing antibodies
(see Appendix III).
In the case of T cells, it is also
possible to keep them proliferating indefinitely in
culture by judicious
application of their specific antigen and non-specific
growth factors such as IL-2 (see Figs 23 and 24). The properties of the resulting
lines or clones have given
much information on the regulation
of normal T-cell function.
Naïve cells Once mature, lymphocytes (B or T) circulate through blood and lymph nodes in search of specific
antigen. These cells can be very long-lived, and divide only very rarely. Such
lymphocytes, which have yet to encounter antigen, are known as naïve or
virgin (see Fig. 17). Naïve T cells enter lymph nodes from blood at special
sites known as high endothelial venules (HEV). They then travel though the
lymph node in search of antigen presented on the surface of antigen- presenting
dendritic cells in the T-cell areas of lymphoid tissues.
Memory cells After lymphocytes encounter antigen they enter
cell division, in order to increase the number of cells specific for that
particular antigen. A proportion of cells then become memory cells. The
migratory paths of memory cells and naïve cells are quite distinct;
memory cells leave blood vessels at the site of an infection, enter tissues and
then travel back to lymph nodes via the lymphatics. Memory cells can
persist for many years, dividing every few months, even in the absence of
further antigen stimulation. Most memory T cells are conveniently distinguished
from naïve T cells by expression of the CD45RO and CD45RA surface markers,
respectively.
Effector cells After
they encounter antigen, a
proportion of lymphocytes differentiate into effector
cells, expressing molecules required to perform their ultimate function in
defending the body against disease. B-cell effectors mostly settle in the bone
marrow, where they produce antibody, and are known as plasma cells. T
cells can become helper cells (TH), cytotoxic cells (CTLs, TC) or
regulatory cells (TREG). Effector T cells migrate to the site of infection,
and usually stop recirculating or dividing further.
NK Natural killer cells are cytotoxic to some
virus-infected cells and some tumours (see also Fig. 42). NK cells express a
special class of polymorphic killer inhibitory receptors (KIRs) which bind
self- MHC and then negatively signal to the cell to prevent activation of
cytotoxicity. NK cells are therefore only activated when cells lose expression
of MHC molecules, such as sometimes occurs during viral infection or tumour
growth. They thus form an important counterpart to cytotoxic T cells (see
below), which kill cells only when they do express MHC molecules. An
intermediate cell type known as the NK-T cell uses a restricted set of T-cell
receptors to respond to bacterial glycolipids presented by CD1 molecules, but
has many of the properties of NK cells.
T cells The subset of lymphocytes that develop within
the thymus (see Fig. 16). All T cells express one form of the TCR with
which they recognize antigen.
Two alternative types of TCR exist,
consisting either of a dimer made up of an α and a β chain or, a γδ dimer (see
Fig. 12).
CD A classification of the molecules found on the
surface of haemopoietic cells based on reaction with panels of monoclonal
antibodies. The profile of CD antigens expressed by cells is used to classify
them. A list of CD numbers is given in Appendix III, but it should be noted
that some older functional names (C3 receptor, Fc receptor, etc.) are still in
use.
Polyclonal activation Stimulation of many clones, rather than the few
or single clones normally stimulated by an antigen. Because the first sign of
activation is often mitosis, polyclonal activators are sometimes known as
‘mitogens’. Several T-cell polyclonal activators are of plant origin, e.g.
concanavalin A (CON A) and phytohaemagglutinin (PHA). Dextran sulphate,
lipopolysaccharide (e.g. Salmonella endotoxin) and Staphylococcus aureus cell wall are normally mitogenic only for B
cells. They have provided a useful tool
for the study of lymphocyte activation.
Cytotoxic T cell (TC) Cytotoxic T cells
kill cells expressing their specific antigen target. The killing is triggered
by binding of the TCR to MHC bound to appropriate antigen peptide
fragments (see Fig. 18). The target cell is killed either by the release of
perforin and granzymes, or by expression of CD154 (also known as Fas ligand) on
the T-cell surface that engages CD95 (Fas) on the target. In both cases, the
target cell dies by programmed cell death (also known as apoptosis). CTLs
are key cells in virus immunity (see Figs 27 and 28) and immune responses
to tumours (Fig. 42). Prolonged stimulation of cytotoxic T cells, e.g. due to
chronic infection or cancer, can lead to cell exhaus- tion, in which large
numbers of T cells persist but have greatly impaired cytotoxic activity and
cytokine production.
Helper T cell (TH) The CD4 T cell is essential for most antibody
and cell-mediated responses (see Figs 18, 19 and 21). CD4 T cells can be
further subdivided on the basis of which cytokines they secrete. TH1 cells, for
example, make cytokines such as IFNγ and TNF-α important for activating
macrophages or delayed hypersensitivity. In contrast, TH2 cells make
cytokines needed for helping B cells to make certain types of antibody,
especially IgE. The most recent T-helper subtype to be defined are confusingly
named TH17 because they secrete the cytokine IL-17. These cells are important
in recruiting neutrophils, and especially in protection against fungal
infection (see Fig. 30), but they are also frequently associated with autoimmunity
(see Fig. 38).
Regulatory T cell (TREG) These cells are the major regulators of the immune response. They can be
distinguished from other T cells by the expression of high levels of CD25 and
the transcription factor FOXP3. “Natural” TREG come directly from the thymus,
and help maintain self- tolerance (Fig. 22). Other types of TREG can be induced
during infection and work by the release of inhibitory cytokines such as IL-10
and TGF-β.
B cells Lymphocytes whose antigen-specific receptor is
antibody (Ig, see Figs 13 and 14). B cells develop in the bone marrow (or liver
in the fetus) where they pass through various stages (pre-B and pro-B cells)
that are required for the full assembly of the antibody molecule (see Fig. 13).
Many cells die during this developmental process due to incorrect antibody
assembly or because they recognize self-antigen B cells produce.
Plasma cells are non-motile and are found predominantly in
bone marrow or spleen. Their cytoplasm is completely filled with an enormously
enlarged rough endoplasmic reticulum devoted to synthesis and secretion of
soluble antibody. Most plasma cells are short-lived (1–2 weeks) but some may
survive much longer. Some antibody formation, especially IgM, does not require
T-cell help, and is called ‘thymus independent’. It usually involves direct
cross-linking of anti- body on the B-cell surface by multivalent antigens such
as bacterial cell wall polysaccharides. T-independent responses tend to be
short- lived and show very weak memory.
PCD Programmed cell death, also known as apoptosis;
a process by which cells are induced to die without damage to surrounding
tissue. A very high proportion of both B and T cells die in this way because
they fail to rearrange their receptor genes properly, or because they threaten
to be ‘self-reactive’ (see Fig. 38). Mutations in CD95, a key receptor
activating PCD in lymphocytes, are associated with a multi-organ autoimmune
disease, illustrating the importance of this pathway in regulating the normal immune response.
