1. Lymphocyte Activation & Immune Tolerance
Pin Ling (凌 斌), Ph.D.
ext 5632;
References:
1. Abbas, A, K. et.al, Cellular and Molecular Immunology (6th ed., 2007), Chapter 9-11

2. Question What is happened to the immune
system if RAG1 & RAG2 are mutated?
Severe Combined Immunodeficiency Disease (SCID)
Lacking functional T & B cells

3. Outline Activation of T Lymphocytes B cell Activation & Ab Production
Immune Tolerance
Summary & Question

4. Key points in T cell activation
Activation of CD4 & CD8 T cells
2. Role of Costimulators in T cell activation
3. Signaling Transduction by the TCR/CD3 complex
4. T cell signal “Attenuation”: Roles of inhibitory receptors & Protein degradation

5. Key Concepts in T cell Activation-I
1. Adaptive immune responses are initiated and mediated
by T-cell activation.
2. Naïve T lymphocytes migrate from Thymus to 2o
Lymphoid organs, whereby encounter Ag presented by
APCs (eg. DCs) and then become activated.
3. T-cell activation requires Two Signals:
- Primary Signal-TCR/CD3 –Ag/MHC complex
- Second Signal (Costimulatory)- Other T cell surface molecules (ex. CD28) interact with ligands from APCs.
4. T cell responses decline after the Ag is eliminated.

6. Activation of Lymphocytes in Lymph Nodes

7. Phases of T cell Responses
IL2 –A T cell autocrine factor

8. Cross presentation (priming) of Ag to CD8 T cells
DC has an unique feature:
Allow protein traffic from endosomal vesicles to the cytosol
Ag-MHC-I presentation
Ingest virus-infected or tumor cells => CD8 T cells

9. Role of CD4 T helper cells in the differentiation of CD8 T cells

10. Functions of co-stimulation in T cell activation

11. T-cell Receptor Signaling

12. The T-cell Immunological Synapse
The interface between
T cells and APC cells
=> Prolong interaction
=> Enhance signaling
transduction

13. IL-2 Expression during TCR Signaling
Cyclosporin A

14. Signal Attenuation by the Inhibitory Receptor (CTLA-4)

15. TCR Signal Termination by Protein Degradation

16. Key Concepts in T cell Activation-II
1. Activated CD4 T helper type -1 (Th1) cells regulate the
cell-mediated immunity (CMI) => Macrophages & CD8 T cells.
Th2 cells help Humoral immunity => B cell activation
2. Differentiation of naïve CD8 T cells requires Signals:
- Ag presentation, Cytokines (eg. IL-12), and Effector CD4 T cells in some cases.
The Best characterized costimulatory pathway:
CD28 (T cell)-B7 (APC) interaction.

17. Outline B cell Activation & Ab Production Immune Tolerance
Activation of T Lymphocytes
B cell Activation & Ab Production
Immune Tolerance
Summary & Question

18. Key points in B cell activation & Ab production
Overview of B cell activation
2. Signaling Transduction by BCR & its Co-receptor
3. Mechanisms of CD4 T helper cell-mediated B cell activation
4. The Germinal Center Reaction:
-Isotype switching
-Affinity maturation (Somatic Hypermutation)

19. Key Concepts in B cell Activation-I
1. B cell activation mediates Humoral Immune Responses.
2. Activating B cells => Ab responses => protein Ag
=> Require CD4 T helper cells
=> These protein Ag => T-dependent (TD) Ag
3. Activating B cells => Ab responses to multivalent Ags
w/ repeating epitopes (lipids, polysaccharides)
=> No CD4 T helper cells
=> These lipid & polysaccharide Ags => T-
independent (TI) Ag
4. Heavy chain isotype switching & Hypermutation are
often seen in T cell-dependent humoral immune responses.
5. Primary & 2nd Ab responses differ qualitatively &
quantitatively.

20. Activation of Lymphocytes in Lymph Nodes

21. Phases of B cell Responses

22. Primary vs. Secondary Ab responses

23. B-cell Receptor Signaling

24. CD21/CR2 complement receptor as a Co-receptor for B cells

25. B cell Responses by cross-linking BCR

26. Events of T-B cell Interaction

27. T-B collaboration & the Hapten-Carrier effect

28. Helper T cell-mediated B cell activation

29. Germinal center reactions in T cell-mediated Ab responses
Germinal centers (2nd
follicle)
1. T-dep B cell activation
2. Somatic
hypermutation
3. Isotype switching
4. Memory B cells

30. Ig Heavy chain isotype switching

31. Ig Heavy chain isotype switching-II
1. AID (Activation-
Induced Deaminase)
, ApeI endonuclease
& UNG (Uracil N
Glycosylase) but not
RAG.
2. Other DNA repair proteins
3. Recognize Ig exon or Switch region

32. Ig Heavy chain isotype switching-III

33. Somatic Hypermutation in Ig V region
AID is required in this process.

34. B cell selection in Germinal Centers
Only B cells w/ a
high affinity for
Ag on follicular
DCs (FDCs)
=> Survive

35. Outline Immune Tolerance Summary & Question
Activation of T Lymphocytes
B cell Activation & Ab Production
Immune Tolerance
Summary & Question

36. Key Concepts in Immune Tolerance
1. Self-tolerance may be induced in immature self-reactive
lymphocytes in primary lymphoid organs (Central tolerance)
or mature lymphocytes in peripheral sites (Peripheral
tolerance).
2. Central Tolerance => Cell Death (T & B cells)
(Negative selection) => Receptor Editing (B cells)
=> A change in functional abilities
(Regulatory T cells)
3. Peripheral Tolerance
Mature lymphocytes  self Ags => No response (Anergy)
=> Cell Death
4. Foreign Ags may be administered in ways that inhibit immune
responses by inducing tolerance.

37. Fates of lymphocytes after encounter with antigens

38. Central vs. Peripheral Tolerance

39. Central T cell Tolerance?

40. T cell tolerance-A transgenic mouse model

41. Mechanisms of T cell Anergy

42. Regulatory T cell-mediated Suppression

43. Self Ag-induced death of peripheral T cells

44. Central & Peripheral B cell Tolerance

45. Features of T cell vs.B cell Tolerance

46. Outline Summary & Question Activation of T Lymphocytes
B cell Activation & Ab Production
Immune Tolerance
Summary & Question

47. SUMMARY 1. T-cell activation requires “Two Signals”:
- Primary Signal-TCR/CD3 –Ag/MHC complex
- Second Signal (Costimulatory)- Other T cell surface molecules (eg. CD28) interact with ligands from APCs.
2. B cell activation mediates “Humoral Immune Responses”.
Isotype switching & Hypermutation are key features
in T cell-dep humoral immune responses.
3. Self-tolerance may be induced in immature self-reactive
lymphocytes in primary lymphoid organs (Central
tolerance) or mature lymphocytes in peripheral sites
(Peripheral tolerance).
4. The failure of self tolerance leads to autoimmune
diseases.

48. Question Have you learned something from
this series of Immunology Lectures?
Yes
More or less
Not Sure
Definitely Not