508 Chapter 15
inappropriately vigorous functioning of regulatory T lympho-
cytes may also promote disease. This is suggested by evidence
that certain viral infections and cancers may protect them-
selves from immunological attack by recruiting the activity of
regulatory T lymphocytes.Lymphokines
The T lymphocytes, as well as some other cells such as
macrophages, secrete a number of polypeptides that serve
as autocrine regulators (chapter 11) of the immune system.
These products are generally called cytokines; the term
lymphokine is often used to refer to the cytokines of lym-
phocytes. When a cytokine is first discovered, it is named
according to its biological activity (e.g., B-cell-stimulating
factor ). Because each cytokine has many different actions
( table 15.7 ), however, such names can be misleading. Sci-
entists have thus agreed to use the name interleukin, fol-
lowed by a number, to indicate a cytokine once its amino acid
sequence has been determined.
Interleukin-1, a family of 11 different molecules, was the
first interleukin discovered. Secreted by macrophages and other
cells of the innate immune system, often in response to acti-
vation of toll-like receptors, these molecules can activate the
T cell system and promote other effects (IL-1 b can circulate toin apoptosis—chapter 3, section 3.5), cause the destruction of
the victim cell’s DNA.
The killer T lymphocytes defend against viral and fun-
gal infections and are also largely responsible for transplant
rejection reactions and for immunological surveillance against
cancer. Although most bacterial infections are fought by
B lymphocytes, some are the targets of cell-mediated attack by
killer T lymphocytes. This is the case with the tubercle bacilli
that cause tuberculosis. Injections of some of these bacteria
under the skin produce inflammation after a latent period of
48 to 72 hours. This delayed hypersensitivity reaction is cell-
mediated rather than humoral, as shown by the fact that it can
be induced in an unexposed guinea pig by an infusion of lym-
phocytes, but not of serum, from an exposed animal.
Helper T lymphocytes are identified in the laboratory by
a surface molecule called CD4. As their name implies, these
cells enhance the immune response; they improve the ability
of B lymphocytes to differentiate into plasma cells and secrete
specific antibodies ( fig. 15.12 ), and they enhance the ability of
killer (cytotoxic) lymphocytes to mount a cell-mediated immune
response. Helper T lymphocytes aid the specific immune
response of B lymphocytes and killer T lymphocytes through
secretion of chemical regulators called lymphokines, discussed
in the next section. For example, helper T lymphocytes secrete
a lymphokine called interleukin-2, which aids the killer T lym-
phocyte response (see fig. 15.17 ).
Regulatory (previously called suppressor ) T lymphocytes,
abbreviated T (^) reg lymphocytes, provide a “brake” on the specific
immune response ( fig. 15.12 ); they inhibit the activity of killer
T lymphocytes and B lymphocytes. Although there is no cell
marker specific for T reg lymphocytes, an important subgroup of
these cells has CD4 as well as CD25 surface markers. The CD25
forms part of the receptor for IL-2 (secreted by helper T cells);
people with a genetic deficiency in CD25, and thus in T reg cell
function, develop severe autoimmune disease and allergy. Also,
T reg lymphocytes have been distinguished by the activation of a
gene known as FOXP3, which codes for a transcription factor
that appears to be required for the development and maintenance
of regulatory T lymphocytes.
The mechanisms by which regulatory T lymphocytes sup-
press immune responses are not completely understood. Immune
suppression requires close proximity or even physical contact
between the T reg cells and their target cells. The release of cyto-
kines, including interleukin - 10 and TGF b (transforming growth
factor beta), from the T reg cells is required in many instances
of immune suppression. In other cases, the regulatory T lym-
phocytes promote destruction of their target cells by releasing
granzymes and perforins, much like the action of killer T cells.
Because regulatory T lymphocytes suppress inappropri-
ate adaptive immune responses, they are required for immune
tolerance to self-antigens and the prevention of autoimmune
diseases (section 15.6). By this reasoning, people may get
autoimmune diseases partly because of inadequate function-
ing of the regulatory T lymphocytes. Indeed, mutations in the
FOXP3 gene and consequent lack of T reg lymphocytes are
known to cause severe autoimmune disease. On the other hand,
Figure 15.12 The effect of an antigen on B and
T lymphocytes. A given antigen can stimulate the production
of both B and T lymphocyte clones. The ability to produce
B lymphocyte clones, however, is also influenced by the relative
effects of helper and suppressor T lymphocytes.
Antibodies
Memory
cell
Plasma
cell
Cytotoxic (killer)
T lymphocyte
Antigen
B lymphocyte
Stem cell
T lymphocyte
Helper
T lymphocytes
Regulatory
T lymphocytes
Clone
+Helper
T lymphocytes