1. Chapter 10
T-cell Maturation, Activation, and Differentiation
Dr. Capers
Immunology

2. Kindt • Goldsby • Osborne
Kuby IMMUNOLOGY
Sixth Edition
Chapter 10
T-Cell Maturation, Activation,
and Differentiation
Copyright © 2007 by W. H. Freeman and Company

3. 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 T-lineage specification

4. 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

5. 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

6. 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

7. T-cell Development
During 3 week development, differentiating T cells pass through stages of development based on surface phenotypes

8. 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

9. T cell development is expensive for host
98% of all thymocytes do not mature, die by apoptosis within thymus

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

13. 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

14. 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

15. 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

16. Go onto
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18. Superantigens Exogeneous Endogeneous 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

20. 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)

22. Treg Cells Shown to inhibit proliferation of other T cells in vitro
CD4+CD25+
Shown to inhibit development of autoimmune diseases

23. 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