Chapter 10

T-cell Maturation, Activation, and Differentiation

Dr. Capers

Kuby IMMUNOLOGYSixth Edition

Chapter 10T-Cell Maturation,

Activation,and Differentiation

Copyright © 2007 by W. H. Freeman and Company

Kindt • Goldsby • Osborne

Progenitor T cells migrate from bone marrow to thymus

T cells can be grown in vitro in absence of thymic fragmentsGrown on bone

marrow stem cells with Notch protein

Notch protein is key in determining T-lineage specification

Progenitor T cells migrate to thymus○ At about 8th or 9th week of gestation in humans

T cell maturation involves rearrangements of the germ-line TCR genes

In thymus, thymocytes proliferate and differentiate

Selection process in thymusPositive selection

○ Survival of only T cells whose TCRs recognize self-MHC molecules

Negative selection○ Eliminates T cells that react too strongly with

self MHC or MHC with self-peptides

T-cell Development

Begins with arrival of small numbers of lymphoid precursors migrating from blood to thymus

○ When they do arrive in thymus, T-cell precursors don’t express signature surface markers (CD3, CD4, and CD8)

○ Do not express RAG-1 or RAG-2 that are necessary for gene rearrangement

T-cell Development

During 3 week development, differentiating T cells pass through stages of development based on surface phenotypes

DN = Double negativeCD4- and CD8-

DP = Double positiveCD4+ and CD8+

C-kit – receptor for stem cell growth factorCD44 – an adhesion moleculeCD25 - alpha chain of IL-2 receptor

T cell development is expensive for host○ 98% of all thymocytes do not mature, die by

apoptosis within thymus

Insertion of rearranged TCR genes suppress other gene rearrangements in these mice

T cell Activation

Initiated by TCR-CD3 complex with processed antigen on MHC molecule

○ CD8+ cells with Class I○ CD4+ cells with Class II

Initiates cascade of biochemical events○ Inducing resting T cell to enter cell cycle,

proliferate, differentiate into memory and effector T cells

T cell Activation

Cascade of biochemical events leading to gene expression:Interaction of signal and molecule (example:

TCR + MHC and antigen)Generation of “second messenger” that

diffuses to other areas of cellProtein kinases and protein phosphatases

are activated or inhibitiedSignals are amplified by enzyme cascades

http://www.youtube.com/watch?v=tMMrTRnFdI4&feature=player_detailpageClick on link to see example

T cell Activation

Gene products after activation○ Immediate genes (1/2 hour of recognition)

Transcription factors (c-Myc, NFAT, NF-κB)

○ Early genes (1-2 hours from recognition)IL-2, IL2R, IL-6, IFN-γ

○ Late genes (more than 2 days later)Encode adhesion molecules

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Superantigens Bind to BOTH the TCR and

MHC Can cause over-activation

Overproduction of TH-cell cytokines, leading to systemic toxicity

Exogeneous Variety of exotoxins

secreted by some Gram+ bacteria

Endogeneous Cell membrane proteins

encoded by viruses

T-Cell Differentiation CD4+ and CD8+ cells leave thymus and enter circulation in

G0 phase

○ Naïve cells (condensed chromatin, little cytoplasm)○ About twice as many CD4+

Naïve cell recognized MHC-antigen complex○ Initiated primary response○ After 48 hours, enlarges into blast cell and undergoes

repeated rounds of cell division○ Differentiate into:

- Effector cells – cytokine secretion, B-cell help- Memory cells – long lived, respond with heightened

activity (secondary response)

Treg Cells

Shown to inhibit proliferation of other T cells in vitro

CD4+CD25+ Shown to inhibit development of

autoimmune diseases

Cell Death and T Cell Populations Apoptosis plays critical role

Deletion of potentially autoreactive thymocytes

Deletion of T cell populations after activation○ Fas and FasL pathway to induce self death