Transcript PowerPoint ****

T细胞生物学
T Cell Biology
Innate and adaptive immunity
3 types of cell，3 types of molecule
T Cell Behaviors
Maturation
Recognition
Activation
proliferation
Differentiation
Apoptosis
Memory
Effector
function
migration
maturation
Stages of lymphocyte maturation
maturation
Pluripotent stem cells give rise to
distinct B and T lineages
Pluripotent stem cells give rise to
distinct B and T lineages.
Hematopoietic stem cells (HSCs) give
rise to distinct progenitors for various
types of blood cells. One of these
progenitor populations (shown here) is
called a common lymphoid progenitor
(CLP). CLPs give rise mainly to B and T
cells but may also contribute to NK
cells and some dendritic cells (not
depicted here). Pro-B cells can
eventually differentiate into follicular
(FO) B cells, marginal zone (MZ) B cells,
and B-1 cells. Pro-T cells may commit
to either the αβ or γδ T cell lineages.
Commitment to different lineages is
driven by various transcription factors,
indicated in italics. ILC, innate lymphoid
cells.
maturation
Maturation of T cells in the thymus
Maturation of T cells in the thymus.
Precursors of T cells travel from the
bone marrow through the blood to
the thymus. In the thymic cortex,
progenitors of αβ T cells express
TCRs and CD4 and CD8 coreceptors.
Selection processes eliminate selfreactive T cells in the cortex at the
double-positive (DP) stage and also
single-positive (SP) medullary
thymocytes. They promote survival
of thymocytes whose TCRs bind self
MHC molecules with low affinity.
Functional and phenotypic
differentiation into CD4+CD8− or
CD8+CD4− T cells occurs in the
medulla, and mature T cells are
released into the circulation. Some
double-positive cells differentiate
into regulatory T cells (see Chapter
15). The development of γδ T cells is
not shown.
maturation
Structure of the T cell receptor
Structure of the T cell
receptor. The schematic
diagram of the αβ TCR (left)
shows the domains of a
typical TCR specific for a
peptide-MHC complex.
The antigen-binding
portion of the TCR is
formed by the Vβ and Vα
domains. The ribbon
diagram (right) shows the
structure of the
extracellular portion of a
TCR as revealed by x-ray
crystallography. The
hypervariable segment
loops that form the
peptide-MHC binding site
are at the top.
maturation
TCR α and β chain gene recombination and expression
TCR α and β chain gene recombination
and expression. The sequence of
recombination and gene expression
events is shown for the TCR β chain (A)
and the TCR α chain (B). In the
example shown in A, the variable (V)
region of the rearranged TCR β chain
includes the Vβ1 and Dβ1 gene
segments and the third J segment in
the Jβ1 cluster. The constant (C) region
in this example is encoded by the
exons of the Cβ1 gene, depicted for
convenience as a single exon. Note
that at the TCR β chain locus,
rearrangement begins with D-to-J
joining followed by V-to-DJ joining. In
humans, 14 Jβ segments have been
identified, and not all are shown in the
figure. In the example shown in B, the
V region of the TCR α chain includes
the Vα1 gene and the second J
segment in the Jα cluster (this cluster
is made up of at least 61 Jα segments
in humans; not all are shown here).
recognition
A model for T cell recognition of a peptide-MHC complex
recognition
Binding of a TCR to a peptide-MHC complex
Binding of a TCR to a
peptide-MHC complex.
The V domains of a
TCR are shown
interacting with a
human class I MHC
molecule, HLA-A2,
presenting a viral
peptide (in yellow). A is
a front view and B is a
side view of the x-ray
crystal structure of the
trimolecular
MHC-peptide-TCR
complex.
recognition
Functions of different antigen-presenting cells
activation
Activation of naive and effector T cells by antigen
activation
Phases of T cell responses
activation
Components of the TCR complex
Components of the TCR
complex. The TCR
complex of MHCrestricted T cells
consists of the αβ TCR
non-covalently linked to
the CD3 and ζ proteins.
The association of these
proteins with one
another is mediated by
charged residues in
their transmembrane
regions (not shown).
activation
Ligand-receptor pairs involved in T cell activation
Ligand-receptor pairs involved in T cell activation. A, The major surface molecules of CD4+ T cells involved in the activation of
these cells (the receptors) and the molecules on APCs (the ligands) recognized by the receptors are shown. CD8+ T cells use
most of the same molecules, except that the TCR recognizes peptide–class I MHC complexes, and the coreceptor is CD8, which
recognizes class I MHC. Immunoreceptor tyrosine-based activation motifs (ITAMs) are the regions of signaling proteins that are
phosphorylated on tyrosine residues and become docking sites for other signaling molecules. CD3 is composed of three
polypeptide chains, named γ, δ, and ε, arranged in two pairs (γε and δε) as shown in Figure 7-8; we show CD3 as three protein
chains.
activation
Ligand-receptor pairs involved in T cell activation
B, The important properties of
the major accessory molecules
of T cells, so called because
they participate in responses to
antigens but are not the
receptors for antigen, are
summarized. CTLA-4 (CD152) is a
receptor for B7 molecules that
delivers inhibitory signals; its
role in shutting off T cell
responses is described in
Chapter 9. APC, antigenpresenting cell; ICAM-1,
intercellular adhesion molecule
1; LFA-1, leukocyte functionassociated antigen 1; MHC,
major histocompatibility
complex;
TCR, T cell receptor.
activation
Functions of costimulators in T cell activation
Functions of costimulators in T cell activation. A, The resting APC (typically dendritic cells presenting self antigens)
expresses few or no costimulators and fails to activate naive T cells. (Antigen recognition without costimulation may
make T cells unresponsive [tolerant]; we will discuss this phenomenon in Chapter 15.) B, Microbes and cytokines
produced during innate immune responses activate APCs to express costimulators, such as B7 molecules. The APCs
(usually presenting microbial antigens) then become capable of activating naive T cells. Activated APCs also produce
cytokines such as IL-12, which stimulate the differentiation of naive T cells into effector cells.
activation
Changes in surface molecules after T cell activation
Changes in surface molecules after T cell activation. A, The approximate kinetics of expression of selected
molecules during activation of T cells by antigens and costimulators are shown. The illustrative examples include a
transcription factor (c-Fos), a cytokine (IL-2), and surface proteins. These proteins are typically expressed at low
levels in naive T cells and are induced by activating signals. CTLA-4 is induced 1 to 2 days after initial activation.
The kinetics are estimates and will vary with the nature of the antigen, its dose and persistence, and the type of
adjuvant.
proliferatio
n Regulation of IL-2 receptor expression and proliferation
Regulation of IL-2
receptor expression.
Resting (naive) T
lymphocytes express
the IL-2Rβγc complex,
which has a moderate
affinity for IL-2.
Activation of the T
cells by antigen,
costimulators, and IL-2
itself leads to
expression of the IL2Rα chain and
increased levels of the
high-affinity IL-2Rαβγ
complex.
clonal
expansion
Clonal expansion of T cells
Clonal expansion of T cells. The numbers of CD4+ and CD8+ T cells specific for microbial antigens
and the expansion and decline of the cells during immune responses are illustrated. The numbers
are approximations based on studies of model microbial and other antigens in inbred mice.
Differentiation
Properties of TH1, TH2, and TH17 subsets of CD4+ helper T cells
Effector
Function
Effector Function
Effector
Function
Effector Function
Effector
Function
Effector Function
apoptosi
s
apoptosis
Memory
Development of memory T cells
Development of memory T cells. In response to antigen and costimulation, naive T cells
differentiate into effector and memory cells. A, According to the linear model of memory T
cell differentiation, most effector cells die and some survivors develop into the memory
population. B, According to the branched differentiation model, effector and memory cells
are alternative fates of activated T cells.
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