Page 639 - Veterinary Immunology, 10th Edition

VetBooks.ir Regulation of Apoptosis

The thymus of the mouse releases about 1 million new T cells into
the circulation every day. (Presumably a cow would produce many

more.) To keep the number of mouse lymphocytes relatively
constant, a million must also die. Likewise, the mouse bone marrow
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releases about 10 B cells daily, and a similar number must die. In
addition, lymphocytes divide in response to antigens. All this
proliferation must be balanced by the removal of cells by apoptosis.

Apoptosis also removes autoreactive lymphocytes and limits the
clonal expansion of lymphocytes during an immune response. This
homeostatic system is carefully regulated because if it fails, excess

lymphocytes may cause lymphoid tumors or autoimmunity. The
regulatory process depends on providing cells with survival
signals. If these are inadequate, cells will die. These regulatory
signals are provided by IL-2, IL-4, IL-9, and IL-21.
Apoptosis is mediated by intracellular caspases. Caspases are

expressed as inactive precursors in lymphocytes. Proteins of the bcl-
2 family modulate their activity. Thus, in a quiescent cell, survival
depends on the ongoing presence of bcl-2. Cytokines also regulate

apoptosis. Survival is signaled through IL-2, IL-4, IL-7, and IL-15,
whereas cell death is signaled through CD95 and TGF-β.
Activated lymphocytes become more susceptible to killing
through TNF and CD95. Thus, activation of T cells enhances
expression of CD95L. However, the CD95 pathway is normally

blocked by stimulatory signals such as those transmitted through
CD28 on T cells and CD40 on B cells. Once these co-stimulatory
signals are lost, activated cells will undergo CD95-induced

apoptosis. This is why unwanted lymphocytes are eliminated at the
end of the immune response.

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