Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1314 Chapter 24: The Innate and Adaptive Immune Systems
3. In clonal inactivation (also called clonal anergy), self-reactive B and T cells
become functionally inactivated when they encounter their self molecule.
4. In clonal suppression, self-reactive regulatory T cells (discussed later) suppress
the activity of other types of potentially self-reactive lymphocytes.
Some of these mechanisms—especially the first two, receptor editing in B cells
and clonal deletion of B and T cells—operate in central lymphoid organs when
newly formed self-reactive B and T cells first encounter their self molecules, and
they are largely responsible for the process called central tolerance. Clonal inactivation
and clonal suppression, by contrast, operate mainly when mature B and
T cells encounter their self molecules in peripheral lymphoid organs, and they
are largely responsible for the process called peripheral tolerance. Clonal deletion,
however, can also operate peripherally, and clonal inactivation can also operate
centrally.
Why does the binding of a self molecule lead to tolerance rather than activation?
The answer is still not completely known. As we discuss later, the activation
of a B or T cell by its antigen in a peripheral lymphoid organ requires more than
just antigen binding: it requires co-stimulatory signals, which are provided by a
helper T cell (discussed later) in the case of a B cell and by an activated dendritic
cell in the case of a naïve T cell. The production of such signals is usually triggered
by exposure to a pathogen, but a self-reactive lymphocyte normally encounters
its self antigen in the absence of such signals. Under these conditions, the lymphocyte
will not only fail to be activated, it will often be rendered tolerant—being
either killed or inactivated, or actively suppressed by a regulatory T cell (see Figure
24–21). In peripheral lymphoid organs, both T cell tolerance and activation
usually occur on the surface of a dendritic cell.
For reasons that are usually unknown, self-tolerance mechanisms sometimes
fail, causing T or B cells (or both) to react against the animal’s own molecules.
immature
lymphocytes
B cell with
altered specificity
1
RECEPTOR
1′
EDITING
self antigens
2
3
CLONAL
DELETION dead
lymphocyte
mature
naïve
lymphocytes
1′ 1′
foreign
antigen
co-stimulatory
signal
foreign
antigen
1′
3
effector or memory
lymphocytes
effector or memory
lymphocytes
4
CENTRAL LYMPHOID ORGAN
self
antigen
3 3
CLONAL
DELETION
4
CLONAL
INACTIVATION
CLONAL
SUPPRESSION
4
4
dead
lymphocyte
inactivated
lymphocyte
suppressed
lymphocyte
regulatory
T cell
PERIPHERAL LYMPHOID ORGAN
Figure 24–21 Mechanisms of immunological self-tolerance. When a self-reactive immature B cell binds its self molecule in the central lymphoid
organ where the cell is produced, it may alter its antigen receptor so that it is no longer self-reactive (cell 1); this process is called receptor editing.
Alternatively, when either an immature B or T cell binds its self molecule in a central lymphoid organ, it may die by apoptosis, a process called clonal
deletion (cell 2). Because these two forms of tolerance (shown on the left) occur in central lymphoid organs, they are called central tolerance.
When a self-reactive naïve B or T cell escapes tolerance in the central lymphoid organ and binds its self molecule in a peripheral lymphoid organ
(cell 4), or in another peripheral tissue, it will generally not be activated, because the binding usually occurs in the absence of sufficient co-stimulatory
signals; instead, the cell may die by apoptosis (often after a period of proliferation), be inactivated, or be suppressed by a regulatory T cell. These
forms of tolerance (shown on the right) are called peripheral tolerance. As discussed later, the cells providing the co-stimulatory signals are
T lymphocytes for B cells and usually dendritic cells for T cells (not shown). For T cells at least, both activation and tolerance in a peripheral lymphoid
organ usually occurs on the surface of a dendritic cell, although the dendritic cells are different in the two cases.
MBoC6 m25.13/24.22