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
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In both vertebrates and invertebrates, many proteins in the Ig superfamily are
also found outside immune systems, where they often function in cell–cell recognition
and adhesion processes, both during development and in adult tissues.
It seems likely that the entire gene superfamily evolved from a primordial gene
coding for a single Ig‐like domain, similar to that encoding β 2 ‐microglobulin (see
Figure 24–36). In present-day family members, a separate exon usually encodes
the amino acids in each Ig‐like domain, consistent with the likelihood that new
family members arose during evolution by exon and gene duplications.
Summary
There are three main functionally distinct classes of T cells. Cytotoxic T cells (T C
cells) directly kill infected cells by secreting perforins and granzymes that induce the
infected cells to undergo apoptosis. Helper T cells (T H cells) help activate cytotoxic
T cells to kill their target cells, B cells to make antibody responses, macrophages
to destroy the microorganisms they harbor, and dendritic cells to activate T cells.
Regulatory T cells (T reg cells) produce suppressive proteins (such as the cytokines
IL10 and TGFβ) to inhibit other immune cells.
All T cells express cell-surface antigen receptors (TCRs), which are encoded by
genes that are assembled from multiple gene segments during T cell development
in the thymus. TCRs recognize peptide fragments of foreign proteins that are displayed
in association with MHC proteins on the surface of antigen-presenting cells
(APCs) and target cells. Naïve T cells are activated in peripheral lymphoid organs
by activated dendritic cells, which secrete cytokines and express peptide–MHC complexes,
co-stimulatory proteins, and various cell–cell adhesion molecules on their
cell surface.
Class I MHC proteins present foreign peptides to T C cells, whereas class II MHC
proteins present foreign peptides to T H cells and T reg cells. Whereas class I MHC
proteins are expressed on almost all nucleated vertebrate cells, class II MHC proteins
are normally restricted to APCs, including dendritic cells, macrophages, and
B lymphocytes. Both classes of MHC proteins have a single peptide-binding groove,
which binds a large set of small peptide fragments produced intracellularly by normal
protein-degradation processes: class I MHC proteins mainly bind fragments
produced in the cytosol, whereas class II MHC proteins mainly bind fragments produced
in endocytic compartments. The peptide–MHC complexes are transported
to the cell surface, where complexes that contain a peptide derived from a foreign
protein are recognized by TCRs, which interact with both the peptide and the walls
of the peptide-binding groove. T cells also express CD4 or CD8 co-receptors, which
recognize invariant regions of MHC proteins: T H cells and T reg cells express CD4,
which recognizes class II MHC proteins; T C cells express CD8, which recognizes
class I MHC proteins.
A combination of positive and negative selection operates during T cell development
in the thymus to help ensure that only T cells with potentially useful TCRs
survive, mature, and emigrate, while all of the others die by apoptosis. The naïve
T H and T C cells that leave the thymus constantly receive survival signals when their
TCRs recognize self-peptide–MHC complexes, but they can only be activated when
their TCRs encounter foreign peptides in the grooves of MHC proteins on an activated
dendritic cell. The natural T reg cells that leave the thymus suppress self-reactive
lymphocytes to help maintain self-tolerance.
The production of an effector T cell from a naïve T cell requires multiple signals
from an activated dendritic cell. MHC–peptide complexes on the dendritic cell surface
provide one signal, by binding to both TCRs and a CD4 co-receptor on a T H or
T reg cell. Co-stimulatory proteins on the dendritic cell surface and secreted cytokines
are the other signals. When naïve T H cells are initially activated on a dendritic cell,
they differentiate into T H 1, T H 2, T FH , or T H 17 effector helper cells or into induced
T reg cells, depending mainly on the cytokines in their environment. T H 1 cells secrete
interferon-γ (IFNγ) to activate macrophages and to induce B cells to switch the class
of Ig they make; T H 2 and T FH cells secrete other cytokines that also induce B cells
to switch Ig class; and T H 17 cells secrete IL17 to promote inflammatory responses
What we don’t know
• What initiates an autoimmune
disease such as type 1 diabetes or
multiple sclerosis?
• When a naïve or memory T or
B cell is activated by antigen and
co-stimulatory signals, how does it
decide whether to become an effector
cell or memory cell? Are there cells
that are pre-committed to becoming
either effector or memory cells, for
example, or is the decision determined
solely by extracellular signals?
• Why do some of us make IgE
antibodies against harmless antigens
and thereby develop hay fever and
allergic asthma, while most of us do
not, and why is the proportion of such
allergic individuals increasing?
• How does a cytotoxic T cell (or NK
cell) avoid being killed by the perforin
and granzymes that it secretes to kill a
target cell?