Chapter 10
T-cell Maturation, Activation, and Differentiation
Dr. Capers
Kindt • Goldsby • Osborne
Kuby IMMUNOLOGY
Sixth Edition
Chapter 10
T-Cell Maturation, Activation,
and Differentiation
Copyright © 2007 by W. H. Freeman and Company


Progenitor T cells
migrate from bone
marrow to thymus
T cells can be grown
in vitro in absence of
thymic fragments
 Grown on bone
marrow stem cells
with Notch protein
 Notch protein is key
in determining Tlineage 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 thymus
 Positive 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 negative
CD4- and CD8-
DP = Double positive
CD4+ and CD8+
C-kit – receptor for stem cell growth factor
CD44 – an adhesion molecule
CD25 - 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 cell
 Protein kinases and protein phosphatases
are activated or inhibitied
 Signals are amplified by enzyme cascades
Click on link to see example
http://www.youtube.com/watch?v=tMMrTRnFdI4&f
eature=player_detailpage
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
Go onto
Next slide
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