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

T CELLS AND MHC PROTEINS
1337
β
α
BCR
α
β
EXTRACELLULAR
SPACE
TCR
ε γ δ ε
Figure 24–45 The invariant chains
associated with BCRs and TCRs.
(A) Each BCR is associated with two
invariant heterodimers, each composed of
an Igα and an Igβ polypeptide chain linked
by a sulfide bond (red). (B) Each TCR is
associated with an invariant CD3 complex
composed of two disulfide-bonded ζ
chains, two ε chains, and one δ and one
γ chain; these chains form homodimers or
heterodimers, as shown.
CYTOSOL
Igα/Igβ heterodimers
ζ
ζ
(A)
B CELL
CD3 complex
co-stimulatory signals produced by another cell are also required, and they are
provided by membrane-bound proteins (see Figure 24–34) and secreted cytokines.
Indeed, signaling through the BCR or TCR with insufficient co-stimulation
can either eliminate the lymphocyte (clonal deletion) or inactivate it, with both of
these mechanisms contributing to self-tolerance (see Figure 24–21). For a naïve T
cell, an activated dendritic cell provides the co-stimulatory signals; these include
the transmembrane B7 proteins, which are recognized by the co-receptor protein
CD28 on the surface of MBoC6 the T n24.108/24.47
cell (Figure 24–47A). For a B cell, an effector T H
cell provides the co-stimulatory signals; these include the transmembrane CD40
ligand, which binds to CD40 receptors on the B cell (Figure 24–47B). The CD40
ligand on effector T H cells acts in two other situations: (1) it acts back on CD40
receptors on the dendritic cell surface to increase and sustain the activation of the
dendritic cell, creating a positive feedback loop; and (2) it acts as a co-stimulatory
signal on the surface of an effector T H 1 cell, allowing the T cell to help activate an
infected macrophage to destroy the pathogens it harbors.
In addition to receptors for co-stimulatory proteins, both B and T cells have
inhibitory proteins on their surface that help regulate the cell’s activity, preventing
excessive or inappropriate responses. Two such proteins expressed by T cells have
attracted great attention because of their roles in suppressing the ability of T cells
to inhibit cancer progression: CTLA4 and PD1 proteins inhibit T cell activity in
different ways, and monoclonal antibodies against either or especially both can
relieve the inhibition and allow T cells to dramatically destroy the tumors in some
patients with metastatic cancer (see Figure 20–45).
(B)
T CELL
Figure 24–46 Early signaling events
in a B cell activated by the binding of
specific foreign antigen to its BCRs. If
the antigen is on the surface of a pathogen
or is a soluble macromolecule with two
or more identical antigenic determinants
(as shown), it cross-links adjacent BCRs,
causing them and their associated invariant
chains to cluster, as shown. A Src‐like
cytoplasmic tyrosine kinase (which can
be Fyn or Lyn) is associated with the
cytosolic tail of Igβ; it joins the cluster
and phosphorylates both the Igα and
Igβ invariant chains (for simplicity, only
the phosphorylation on Igβ is shown).
A transmembrane protein tyrosine
phosphatase called CD45 is also required
to remove inactivating phosphates from
these Src‐like kinases (not shown). The
resulting phosphotyrosines on Igα and Igβ
serve as docking sites for another Src‐like
tyrosine kinase called Syk, which becomes
phosphorylated and thereby activated to
relay the signal downstream.
The pathway from TCRs is similar
(including a requirement for CD45), except
that the first Src‐like kinase is Lck, which is
associated with a CD4 or CD8 co-receptor
and phosphorylates tyrosines on all the
CD3 polypeptide chains shown in Figure
24–45B; the second Src‐like kinase is
ZAP70, which is homologous to the Syk
kinase in B cells (Movie 24.14).
BCR
antigenic determinant
invariant chains
β α α β β α α β
plasma membrane
β α α β
of B cell
β
α
α
β
EXTRACELLULAR
SPACE
CYTOSOL
active Src-like kinase
P
P
P
P
P
P
P
P
inactive Syk kinase
active Syk kinase relays
signal downstream