Transcript T cell Development

Ch.7 The Development of T Lymphocytes
Copyright © 2009 by Garland Science Publishing
T-cell development in thymus
Thymus , T cell and Aging
T cells develop in the thymus
The size of thymus is gradually decreased from the birth, and rapidly
reduced from puberty
Thus, whole T cell repertoire is decreasing with aging
3days
70 years
T cell development
Thymocyte Development and Differentiation
outer cortex
DN3
DN2
DN4
TcR beta selection
DN1
inner cortex
death by neglect
inadequate
TCR signaling
DP
MHC Class II
recognition
positive
selection
CD4 committed DP
cortical
epithelial cell
MHC Class I
recognition
negative
selection
CD8 committed DP
lymphoid
progenitor
hematopoietic
precursor
medulla
periphery
periphery
adapted from Germain, 2002, Nature Review Immunology
Positive selection
• Self-MHC-Restriction
Epithelial cells in thymus
Negative selection
• Self-Tolerance
Signal Transduction
Negative Selection
Positive Selection
TCR signal
Death by Neglect
About 98% of thymocytes die by apoptosis for their failure in
making productive TcR gene rearrangement or failure in receiving
survival signal (adequate TcR signal)
T-cell lineage commitment
Notch
• 4 isotypes in vertebrate: Notch 1~4
• Single-pass receptor
• Ligands: Delta (-like), Serrate
(Jagged)
• Required for early development of
thymocytes
• Intracellular domain of Notch
(Notch-IC) delivers the signal
Notch-1 signaling
alpha:beta vs gamma:delta T cells
• gamma:delta T cells are
responsible for about 5% of
total peripheral T cells
• gamma:delta T cells are
involved in innate immunity
• Rearrangement of TcR
gamma and delta precedes
that of TcR beta
Ig Heavy chain vs TcR beta rearrangement
• TcR beta chain rearrangement is more efficient for generating
productive in-frame chain
• Why?
CD4 SP: Gata3, ThPOK
CD8 SP: Runx1, Runx3
AIRE : autoimmune regulator
causes several hundreds of tissue specific genes to be transcribed
in the thymic stromal cells