Chapter 10

T-Cell Maturation, Activation, and Differentiation

本章大綱 :

1. T-Cell Maturation and the Thymus2. Thymic Selection of the T-Cell Repertoire3. TH-Cell Activation4. T-Cell Differentiation5. Cell Death and T-Cell populations6. PeripheralT-Cells

T-Cell Maturation and the Thymus

The Human Lymphoid System

The Normal Rat Thymus

The Thymusstromal cells:

m

aturation

Two-step Selection Process of Thymocytes

Positive Selection: permits the survival of only those T cells whose TCRs recognize self-MHC molecules.

Negative Selection: eliminates T cells that react too strongly with self-MHC or with self-MHC plus self-peptides.

Thymic stromal cells, which express high levels of class I and class II MHC molecules, play a role in this process.

- Any developing thymocytes that are unable to recognize self-MHC molecules or that do have a high affinity for self-Ag plus self-MHC (or self-MHC alone) are eliminated by programmed cell death.

- Thus, only those cells whose receptors recognize a self- MHC molecules plus foreign Ag are allowed to mature.

- An estimated 95%--99% of all thymocyte progeny undergo programmed cell death within the thymus without ever maturing.

Various features used to characterize the pathway of T-cell development in the thymus

1. TCR-gene rearrangement2. Activity of genes, such as RAG-1 and RAG-2, that are involved in TCR rearrangement3. Display of surface Ags specific for T-cell differentiation. TCR CD4 CD8

- Most of the immune thymocytes in the thymus die either because they make an unproductive TCR-gene rearrangement or because they fail positive or negative selection.

- Mature T-cell populations are produced and move to the peripheral lymphoid organs.

- Most T cells express the TCR and either CD4 or CD8. A few T cells express the TCR; most of these lack both CD4 and CD8.

Proposed Pathways for Murine T-cell Development in the thymus

receptor for stem-cell growth factor

adhesion molecule

IL-2R

Time Course of Appearance of Thymocytes and Thymocytes During Mouse Fetal Development

General Structure of the Pre-TCR and Effects of Activating it

Effects of Signal Transduction through the pre-TCR

- A productive TCR -chain rearrangement has been made and selects those thymocytes expressing the chain for further expansion and maturation

- Suppresses further rearrangement of TCR -chain genes, resulting in allelic exclusion of the chain

- Enhances rearrangement of the TCR chain

- Induces developmental progression to the CD4+CD8+ double-positive state

Thymic Selection of the T-Cell Repertoire

The Thymus Selects for Maturation Only Those T Cells Whose TCRs Recognize Ag Presented on Target Cells with the Haplotype of the Thymus

Positive and Negative Selection of Thymocytes in the Thymus

Acquisition of MHC Restriction Depends on Interaction of Immature Thymocytes with Class I or

Class II MHC Molecules on Epithelial Cells

CD8+ T Cells Only Mature in Transgenics with the Haplotype (H-2k) Corresponding to the MH

C Restriction of the TCR Transgene

Negative Selection of Thymocytes Requires Self-Ag Plus Self-MHC

TH -Cell Activation

Some Common Themes in Signal Transduction

1. The involvement of a receptor.2. The generation of second messengers.3. The action of protein kinases and protein phosphatases.4. The induced assembly of critical components of a signal transduction pathway.5. Cascades.6. The involvement of large and small G proteins.7. The default setting for signal transduction pathways is OFF.

Initial Steps in TH-Cell Activation

ITAM: immunoreceptor tyrosine-based activation motif

Overview of Signal Transduction During T-Cell Activation

Mechanism of Immunosuppression by Cyclosporin A (CsA) and FK506

TH- Cell Activation Requires a Co-stimulatory Signal Provided by APC

Naïve T Cells Require 2 Distinct Signals for Activation and Proliferation into Effector Cells

- The initial signal (signal 1) is generated by interaction of an antigenic peptide with the TCR-CD3 complex.

- A subsequent Ag-nonspecific co-stimulatory signal (signal 2) is provided primarily by interactions between CD28 on the T cell and members of the B7 family on the APC.

no signal 2no signal 2

Clonal Expansion versus Clonal Anergy

CD28CD28

no signal 2no signal 2

The Resulting Anergic T Cells Cannot Respond to Normal APCs

signal 2signal 2

signal 1signal 1

signal 2signal 2

signal 1signal 1

Superantigen-mediated Crosslinkage of T-cell Receptor and Class II MHC Molecules

various bacterial Mls Ags encoded by mouse exotoxins mammary tumor virus

T-Cell Differentiation

Up-regulation of IL-2 and High-affinity IL-2R after the Activation of a TH Cell

TH Cells:

TH1 subset: secretes IL-2, IFN-, and TNF- cell-mediated functions

TH2 subset: secretes IL-4, IL-5, IL-6, and IL-10 helper for B-cell activation

T Cell Activation Induced by Different APCs

Cell Death and T-Cell Populations

T Cell Death Trigged by Many Different Induction Pathways

Fas-induced Cell Death

AICD: activation induced cell death

Peripheral T Cells

T cells

- In humans, T cells < 5%- In mice, T cells in lymphoid organs ~ 1% to 3%, abundant in the skin and intestinal epithelium

intraepidermal lymphocytes: - 1% of the epidermal cells in the skin of mice are T cells. - TCR-CD3 (+), Thy-1 (+), CD4 (), CD8 ()

intestinal intraepithelial lymphocytes (iIELs): - TCR-CD3 (+), Thy-1 (+), CD8 (+)

Tissue T cells

- T cells in epithelial tissues appear not to circulate and remain fixed in the tissue sites.

- The T cells in different epithelial tissue sites appear to express different Vand V gene segments with limited diversity.

- This selective expression of different V gene segments in different epithelial tissues may reflect a specialization of these T cells to respond to certain types of Ags that tend to be found at these sites.

Ligands Recognized by T Cells: - Elusive (令人困惑的 ) - Some T cells may bind directly to a protein Ag without requiring Ag processing and presentation together with MHC.

Function of T Cells: - Not clear - Some T cells may be uniquely suited to respond to heat-shock proteins and may have evolved to eliminate damaged cells as well as microbial invaders.

The End