Chapter 10- T-cell maturation, Activation, & Differentiation

1. Chapter 10- T-cell maturation, Activation, & Differentiation • Where we’re going- • Define these words • Positive and negative selection • Some terms for the steps along the way to maturity • Be in awe of how complex activation is (not really- hard to test!), and understand the bottom line

2. What’s this?

3. The job of making functional T cells • Precursor mature, but naïve T cell (Th or Tc), activate, differentiate. • Doesn’t react to self • Binds to MHC • Able to respond to an antigen that it’s never met! (is that weird, or what???)

4. DN= double negative

7. So some thought experiments • If a is able to recognize both an A and B haplotype, but the thymus only shows it the B haplotype- what kind of T cells will you produce?

8. Key point- the lymphocytes are not recognizing the A haplotype, because they are maturing in a B haplotype environment.

9. Lots of TCR diversity- Some can’t bind MHC, or bind too well. Some respond to self Ag’s Double Positive thymocyte

10. Two super-cool experiments supporting this story

11. Another thought expt. • If a T cell needs to see MCH I k haplotype, but you only show it MHC I d haplotype- will it develop?

12. Genes injected into eggs- major TCR genes made! Most thymocytes carry this TCR!

13. Another thought experiment • If a T cell is preset to respond to an antigen, and it sees that antigen in the thymus- what happens?

14. H-Y is male specific antigen! Again, you only produce 1 type of T cell- should have either CD4+ or CD8+, and it binds to H-Y Ag!

15. Activation • Activation of Thelper cells: We know that Th are needed for both B cell activation and Tc activation.- We’re concentrating on Th cell activation here. • Common features: pp 229-231: • -receptor-ligand interaction; • Transduction through a G protein- active w/GTP bound • Production of 2nd messengers: cAMP or Ca++. • Protein kinases & phosphatases activate or inhibit proteins. • The bottom line is IL2 secretion and response to its own secretion by an IL2 receptor and proliferation

16. Lck= lymphocyte kinase

20. Chokingly complex- what to remember • Importance of CD3 and its ITAMS • Phosphorylation activates proteins • Cascade • G proteins, • 2nd messengers • Gene activation • Ongoing proliferation- IL2 and its receptor.

21. Control! CTLA 4 acts to prevent overstimulation!

22. “Signal 1 and 2”- TCR activation isn’t the whole story • TCR activation is necessary, but not sufficient, to produce activation. It is called “signal 1”. • The T cell also needs “signal 2”- CD28-B7 interaction. • Its absence produces clonal anergy

30. Differentiation • A cell then becomes an effector cell, or a memory cell. • Effector Th cell secretes certain cytokines- 2 basic types (or maybe three, with suppressors!)- the cytokines released affect whether the response is primarily antibody or primarily cell-mediated. • Effector Tc cells can kill their targets • Memory cells proliferate more readily upon a second stimulation.

32. Key Points to chapter 10 • Define maturation, activation, differentiation • Positive and negative selection, double negative and double positive thymocyte • Key components to activation signaling: • Phosphorylation • GTP • Key 2nd messenger- Ca++ • The major effects- activating transcription factors • Bottom line- IL2 and IL2R for proliferation

33. Signal 1 and 2 & differentiation • Know signal1 and 2, and anergy • Differentiated Tc cells can now kill target • Th effectors do their work mainly by cytokine production • Memory cells- long-lasting, require less stimulation to activate/differentiate. • Review of superantigens