2. T Cell Development
• Mature CD4* and CD8+ T cells are exported from the thymus to
secondary lymphoid organs
• Notch signaling stimulated by thymic epithelial cells commits CLPs
towards the T cell lineage
• Bone marrow
• Primary Lymphoid Organ
• source of CLPs
• Travel to the thymus for T cell development
3. T Cell Development
• Thymus
• Primary Lymphoid Organ
• Development: V/D/J recombination and antigen receptor assembly
• Maturation (T cell selection): DN, DP, and SP phases
• Mature T cells are to secondary lymphoid organs
6. T Cell Development
DN thymocytes express pTα to test
functionality of recornbined ß chain
during β-selection:
7.
8. • ure
• ummaryan ey on s
• T cell progenitors undergoing development in the thymus must pass three major checkpoints to ensure that recombined TCRs are
(I) MHC-restricted and (2) non-autoreactive before forming mature naive CD4* or CD8* T cells.
• ß-selection
• o Acts on double negative thymocytes to test successful rearrangement of TCRß chain
• 0 Antigen independent
• • Positive selection
• o Acts on double positive thymocytes to test recognition of self MHC by full TCR (rearranged TCRa + TCRß chains)
• o Antigen dependent (self peptide:self MHC)
• Negative selection
• o Acts on positively selected thymcxytes to eliminate autoreactive full TCR
• o Antigen dependent (strong affinity of TCR to self peptide:self MHC)
• o End result = functional and safe TCRs that can be used to present foreign peptide on self MHC
9. T Cell Signaling + Activation
• TCR recognition of peptide-MHC translates the microbial world into T
cell activation
10. T Cell Signaling + Activation
• Central goals of a successful immune responses:
1. Recognize pathogens (detection)
2. Produce effector molecules in response to infection (activation)
3. Deploy effector mechanisms that destroy pathogens
• Direct cytotoxicity (cellular immunity, CD8+ T cells)
• Indirect communication (cytokine production, helper CD4+ T cells)
11. Commonly used signal transduction pathway components
1. Transmembrane receptors receive extracellular ligands (input) and
convert them to intracellular signaling pathways (output)
12. 2. Kinases add free phosphate to activate target proteins (intracellular
domains of receptors, membrane lipids, other kinases)
Important TCR kinases: Lck, ZAP-70, PI3K, PKC-θ
13. 3. Kinases phosphorylate scaffold proteins, allowing them to assemble
protein complexes for signaling
14. 4. Small G proteins can be switched on/off depending on whether GTP
or GDP is bound
21. • S1 P: sphingosine-I-phosphate (functions similarly to chemokine)
• SIPRI: SIP receptor expressed by T cells
22.
23.
24.
25.
26.
27. B Cell Development
5a. B Cell Development
• Immunoglobulin structure recap
• Bone marrow and splenic development
• B cell selection
5b. B Cell Signaling + Activation
5C.B Cell + Antibody Function
28.
29. Q: How does a CLP turn into a functional B cell?
I. Must recognize foreign soluble antigens (no MHC restriction!)
2. Must be non-reactive to self antigens expressed by healthy
tissue
30.
31.
32.
33.
34.
35.
36.
37. mature B cell subsets:
. Follicular B cells
• Re-circulate the and B cell follicles Of
Marginal zone (MZ) B cells
• Positioned at interface between
white and red pulp of spleen
• First to antigens/pathogens
circulating in
38.
39. • Lecture 5a: Summary an Key Points
• cell progenitors undergoing development in the bone marrow and spleen must pass three major checkpoints to insure that
recombined BCRs are non-autoreactive before forming mature naive B cells.
• Pre-BCR
• Acts on large pre-B cell to test successful rearrangement Of heavy Chain
• Antigen-independent
• Negative selection of immature B cells in bone marrow
• Acts on immature B cells to test autoreactivity to self antigens present in the bone marrow
• Antigen-dependent
• Establishes central tolerance
• Result: immature B cells that are allowed to exit bone marrow and migrate to the spleen
• Negative selection Of transitional B cells in spleen
• Acts on transitional B cells to test autoreactivity to self antigens present in spleen
• Antigen-dependent
• Establishes peripheral tolerance
• Result: mature naive B cells (marginal or follicular)
40. B Cell Signaling + Activation
• 5b. B Cell Signaling + Activation
BCR signal transduction pathways
T-dependent vs. antigens
T cell help to B cells
Germinal center formation somatic hypermutation + affinity maturation,
class switching
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58. • GC B cells can also undergo class switch recombination to change
antibody isotypes.
59. • Germinal centers yield higher quality antibodies that those produce in
the first responses B cell responses to primary infection
60. • B cells transduce signals through their BCR with similar logic to T cell/TCR signaling, but undergo different activation processes according to the type of cognate antigen.
• • BCR signaling
• o Similar to TCR; modules of B cell activation include cytoskeletal, adhesion, and transcriptional alterations
• 0 Transcriptional activation: PLC-Y induces NEAT and AP-I
• o Other signals (B cell co-receptor, TLRs, CD21R) also influence transcriptional outputs of B cells (NF-KB, STAT3)
• • Thymus-independent (Tl) vs. thymus-dependent (TD) antigens
• 1.
• 2.
• Tl antigens
• o Typically non-protein polyvalent molecules (polysaccharides on bacteria, other microbes)
• 0 Require T cell help from
• o Can induce plasmablast, plasma cell (phase 1) or germinal center B cell (phase 2) differentiation
• o GC B cells undergo somatic hypermutation and class switch recombination that finely tune long-term antibody
• responses to a given pathogen
• TD antigens
• o Can still initiate antibody responses (phase 1 response)
