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

1336 Chapter 24: The Innate and Adaptive Immune Systems
which is critical for the activation of macrophages to destroy pathogens that either
invaded the macrophage or were ingested by it; the IFNγ can also induce B cells
to switch the class of Ig they are making. Naïve T H cells activated in the presence
of IL4 develop into T H 2 cells. These effector cells are important for the control
of extracellular pathogens, including parasites. They stimulate B cells to undergo
somatic hypermutation and to switch the class of Ig they produce: for example,
the T H 2 cells themselves produce IL4, which can induce B cells to switch from
making IgM and IgD to making IgE antibodies, which can bind to mast cells, as
discussed earlier. Naïve T H cells activated in the presence of IL6 and IL21 develop
into follicular helper T cells (T FH ), which are located in lymphoid follicles and
secrete a variety of cytokines, including IL4 and IL21; these cells are especially
important for stimulating B cells to undergo Ig class switching and somatic hypermutation.
Naïve T H cells activated in the presence of IL6 and TGFβ develop into
T H 17 cells. These effector cells secrete IL17, which recruits neutrophils and stimulates
epithelial cells and fibroblasts in the skin and gut to produce pro-inflammatory
cytokines. T H 17 cells are important in controlling extracellular bacterial
and fungal infections and in wound healing, but they can also have a major role in
autoimmune diseases and allergy.
In some cases, naïve T H cells that encounter their antigen in a peripheral lymphoid
organ in the presence of TGFβ and the absence of IL6 develop into induced
regulatory T cells (T reg cells), which suppress rather than help immune cells; as
mentioned earlier, natural T reg cells develop in the thymus during thymocyte
development (see Figure 24–41). In either case, the T reg cells suppress the development,
activation, or function of most other types of immune cells, by means of
both secreted suppressive cytokines such as IL10 and TGFβ and inhibitory proteins
on the T reg cell surface. Induced T reg cells seem mainly to suppress immune
responses to foreign antigens—preventing responses to harmless ingested or
inhaled antigens and limiting responses against pathogens to avoid excessive
responses that cause unwanted pathology; natural T reg cells are needed to prevent
immune responses to self molecules (see Figure 24–21). T reg cells express the
transcription regulator FoxP3, which serves as both a marker of these cells and a
master controller of their development: if the gene encoding this protein is inactivated
in mice or humans, the individuals fail to produce T reg cells and develop a
fatal autoimmune disease involving multiple organs—findings that establish the
crucial importance of T reg cells in self-tolerance.
Both T and B Cells Require Multiple Extracellular Signals
For Activation
Foreign antigen binding to BCRs or TCRs initiates the process whereby the T and
B cells are stimulated to proliferate and differentiate into effector or memory
cells. As mentioned earlier, these antigen receptors do not act on their own: they
are stably associated with invariant transmembrane polypeptide chains that are
required to relay the signal into the cell. In B cells, these are called Igα and Igβ
(Figure 24–45A), while in T cells they exist in a complex called CD3, composed
of four types of polypeptide chains (Figure 24–45B). In both cases, the associated
proteins help convert extracellular antigen binding to the TCR or BCR into intracellular
signals, and they do so in similar ways.
Antigen binding to BCRs or TCRs clusters these receptors and their associated
invariant chains (and CD4 or CD8 co-receptors in the case of TCRs). This clustering
activates a Src family cytoplasmic tyrosine kinase to phosphorylate tyrosines
on the cytoplasmic tails of some of the invariant chains. The phosphotyrosines
then serve as docking sites for a second cytoplasmic tyrosine kinase, which
becomes phosphorylated and activated by the first kinase; the second kinase then
relays the signal downstream by phosphorylating other intracellular signaling
proteins on tyrosines. Some of these early events in the signaling pathway activated
by BCRs are shown in Figure 24–46.
Signaling through BCRs or TCRs and their associated proteins alone is not
sufficient to activate a lymphocyte to proliferate and differentiate. Extracellular