chapter 10 t-cell maturation, activation, and differentiation dec 7 & 12, 2006 mhc cd4/cd8 tcr
TRANSCRIPT
Chapter 10
T-Cell Maturation, Activation, and Differentiation
Dec 7 & 12, 2006
MHC
CD4/CD8TCR
你需要學習的課題:
1. 什麼叫做 positive selection 及 negative selection ? 它們產生什麼結果?
2. T 細胞需要 costimulatory signals 才得完全活化。
3. 什麼叫做 clonal anergy ?
4. Superantigen 有何性質及作用?
5. T 細胞分化及其 subpopulations 。
6. T 細胞凋亡。
Two-step Selection Process of Thymocytes
Positive Selection: permits the survival of only those T cells whose TCRs recognize self-MHC molecules. generation of a self-MHC-restricted repertoire of T cells
Negative Selection: eliminates T cells that react too strongly with self-MHC or with self-MHC plus self-peptides. generation of a T-cell repertoire that is self-tolerant
Thymic stromal cells, which express high levels of class I and class II MHC molecules, play a role in this process.
Thymic Stromal Cells Play Essential Roles in Positive and Negative Selection
Stromal cells:(expressing Notch ligand)
produce regulatory factors and express high levels of class I and class II MHC molecules
m
aturation
receptor for stem-cell growth factor
adhesion moleculeinvolved in homing
chain of IL-2R
(double negative; CD4-CD8-)
recombination-activating gene(RAG-1/2)
Development of T Cells in the Mouse
[CD3-, CD4-, CD8-]
H
L
< 5%
positive selection
negative selection
Pre-TCR (pre-T/ TCR) Activates Signal Transduction Pathways
Thymic Selection of the T-Cell Repertoire
Positive Selection Ensures MHC Restriction
death by neglect !
(double positive cells)
class Iclass II
Negative SelectionEnsures Self-tolerance
chimeric mouse
irradiated
(source for cytotoxic T cells)
Thymus only selects for T cells whose TCRs recognize Ag presented on target cells with the haplotype of the thymus
infect with LCMV
Positive Selection Requires Binding of Thymocytesto Class I or Class II MHC Molecules
CD8+ T cells only mature in transgenics with H-2k corresponding to the MHC restriction of the TCR transgene
→ Interaction between TCR and self-MHC on immature thymocytes is required for positive selection.
Negative Selection of Thymocytes Requires Both Self-peptide & Self-MHC
♂ ♀ → Interaction between TCR and MHC + peptide on immature thymocytes is required for negative selection.
→ H-Y-reactive thymocytes were self-reactive in the male mice and were eliminated.
A Paradox in Positive and Negative Selection
The T cells which recognize self-MHC :
after positive selection → survival
↓
after negative selection → death
What is left ???
Study of Thymic Selection in Vitro
gestational age of day 16
consisting of CD4-CD8- thymocytes
↓
Study the development
of T cellsin vitro
TAP deficient cells (described in Chapter 8 p. 211)
- RMA-S cell line is an antigen processing-defective tumor cell line. It expresses only ~ 5% of the normal levels of class I MHC on the membrane, although the cells synthesize normal levels of class I chains and 2M.
- Addition of pre-digested peptides to RMA-S cells restores the expression of class I MHC molecules on the membrane.
Effect of Peptides in Thymic Selection
TAP -/- mouse
very few CD8+ cells
When a diverse peptide mixture is added to the culture, the CD8+ T-cell restoration is greater than when a single peptide is added.
dependent on TCR-peptide-class I interactions
recognizes a specific MHC- LCMV peptide
unable to form peptide-MHC complexes unless peptide is added
avidity hypothesis(quantitative)
vs
differential-signaling hypothesis
(qualitative)
Models for the Role of CD4/CD8 Coreceptors in DP → SP (double positive to single positive) T Cells
The central event in the generation of both humoral and cell-mediated immune responses is the activation and clonal expansion of TH cells.
Interaction of a TH cell with Ag initiates a cascade of biochemical events that induces the resting TH cell to enter the cell cycle, proliferating and differentiating into effector cells or memory cells.
TH -Cell Activation
TCR Engagement Initiates Multiple Signaling Pathways
Overview of Common Themes in Signal Transduction (Chapter 1 p.11)
(hydrophobic)
Multiple Signaling Pathways Are Initiated by TCR Engagement
ITAM: immunoreceptor tyrosine-based activation motif
Activation of the small G protein, Ras
Immediate genes, expressed within 30 min of Ag recognition, encode a number of transcription factors.
Early genes, expressed within 1 – 2 hr of Ag recognition, encode cytokines & cytokine receptors.
Late genes, expressed more than 2 days after Ag recognition, encode various adhesion molecules.
Co-stimulatory Signals Are Required forFull T-cell Activation
Naïve T cells require 2 distinct signals for activation and proliferation into effector cells
Signal 1 the initial signal, is generated by interaction of an antigenic peptide with the TCR-CD3 complex.
Signal 2 a subsequent Ag-nonspecific co- stimulatory signal, is provided by interactions between CD28 on the T cell and members of the B7 family on the APC.
TH-cell Activation Requires a Co-stimulatory Signal Provided by APCs
CD28 is expressed by both resting and activated T cells.
B7 (B7-1 and B7-2) are constitutively expressed on dendritic cells, and induced on activated macrophages and activated B cells.
CTLA-4 is expressedon activated T cells.
B7-1 (CD80)
B7-2 (CD86)(CD152)
CD28 & CTLA-4 act antagonistically.
+
-
Clonal Anergy Ensues if a Co-stimulatory Signal Is Absent
Clonal Anergy (Unresponsiveness):
- inability of cells to proliferate in response to a peptide-MHC complex
- If a resting TH cell receives the TCR-mediated signal (signal 1) in the absence of a suitable co-stimulatory signal (signal 2), the TH cell become anergic.
- In the presence of both signal 1 and signal 2, clonal expansion results.
CD28CD28 no signal 2no signal 2
no signal 2no signal 2
inductionof B7 is inhibited.
The Resulting Anergic T Cells Cannot Respond to Normal APCs
signal 1signal 1
signal 2signal 2
signal 1signal 1
signal 2signal 2
Differences in the Properties of 3 Kinds of Professional APCs
Activation of a TH Cell Up-regulates Expression of IL-2 and IL-2 Receptor, Leading to the Entry
of the T Cell into the Cell Cycle
The co-stimulatory signal increases the half-life of the IL-2 mRNA
↓IL-2 100 x ↑
effector T → TH & T Cmemory cells
entry into cell cycle
Effector TH cells: short-lived
TH1 subset: - secretes IL-2, IFN-, and TNF- - responsible for cell-mediated functions, such as delayed-type hypersensitivity and the activation of CTL
TH2 subset: - secretes IL-4, IL-5, IL-6, and IL-10
- helper for B-cell activation
Memory TH cells: long-lived
- Less stringent requirements for activation due to the expression of high levels of numerous adhesion molecules
Regulatory T cells (Treg): CD4+CD25+ cells that inhibit
the proliferation of other T-cell populations in vitro.
Superantigen-mediated Crosslinkage of TCR and Class II MHC Molecules
Exogenous superantigens :
exotoxins secreted by G(+) bacteria, e.g., staphylococcal enterotoxin A & B (SEA, SEB)
Endogenous superantigens:
cell-membrane proteins encoded by certain viruses that infect mammalian cells, e.g., mouse mammary tumor viral (MMTV) protein
- Viral or bacterial proteins that bind simultaneously to particular Vsequences of TCR and to the chain of a class II MHC molecule – induce poly- clonal T-cell activation & proliferation
Programmed Cell Death Is an Essential Homeostatic Mechanism
normal apoptoticthymocyte thymocyte
Two Pathways to T-cell Apoptosis
Fas-associated protein with death domain
AICD : activation-inducedcell death
TCR-mediated negative selection:
apoptosis-inducing factor
apoptotic protease-activating factor 1