T Cell (and B cell) Activation and Signalling

Question 1

T cells need 3 signal for activation

Answer 1

1. TCR signalling
2. Co-stimulatory signalling
3. Cytokine signalling (autocrine and paracrine)

Question 2

CD4 T helper cells interact w/ antigenic peptide via…

Answer 2

-class II MHC on APC

Question 3

CD8 cytotoxic T cells interact w/ antigenic peptide via…

Answer 3

-class I MHC on target cell

Question 4

Immediate, early, late genes in T cell activation

Answer 4

• Immediate genes-expressed within 30 minutes of TCR signalling (e.g.. TFs)
• early genes-expressed within 1-6 hrs of TCR signalling (e.g. cytokines)
• late genes-expressed more than 2 days after TCR signalling (eg. adhesion molecules)

Question 5

IL-2R and IL-2 expression

Answer 5

-allows autocrine T cell growth, cell cycle progression and differentiation into memory cells and effector cells

Question 6

TCR/CD3 Complex signalling- Major events

Answer 6

• phospholipase Cgamma activation
• increase in intracellular calcium concentrations
• protein kinase C activation
• nuclear translocation of NF-kappaB
• activation of Ras/mitogen activated protein kinase (MAPK) pathway

Question 7

What is involved in signal transduction that leads to T cell activation

Answer 7

• TCR/CD3 complex
• CD4/CD8 co-receptors
• accessory molecules (e.g. CD2, CD28, CD45)

Question 8

TCR/CD3 Complex signalling-CD45

Answer 8

-cell surface phosphatase that catalyzes the dephosphorylation of an inhibitory Tyr residue on p56lck (and p59fyn)

Question 9

TCR/CD3 Complex signalling-calcium

Answer 9

• engagement of single TCR by peptide results in intracellular Ca release
• max Ca release is achieved in CD4/Cd8 T cells when as few as 10 TCRs are engaged

Question 10

Immunological Synapse

Answer 10

-TCR/CD3 complex molecules on the inside and adhesion molecules on the outside of the ring

Question 11

Positive Costimulatory Signalling

Answer 11

• activation of naive T cell requires costimulatory signal provide by cd28 interaction with B7 family members on APC
• CD28 on surface of activated T cells as disulphide linked homodimer
• B7-1 (CD80), B7-2 (CD86) found on dendritic cells, activated macs, activated B cells
• CD28 and TCR signalling synergize-augment cytokine production by enhancing gene Tc and stabilizing mRNA

Question 12

Negatively Costimulatory Signalling

Answer 12

CTLA4 found only on activated T cells

• structurally similar to CD28, binds B7 family members
• provides an inhibitory signal (phosphatase activation) that down-regulates T cell activation
• expression proportional to strength of CD28 signaling

Question 13

CTLA4 induction

Answer 13

• induced within 24h of TCR engagement

- out-competes CD28 for B7 molecules because of its higher affinity for these molecules

Question 14

Complex of 3 proteins making up B cell coreceptor

Answer 14

CD19
CR2
TAPA-1

Question 15

CD19

Answer 15

-has a long cytoplasmic tail that contain docking sites for intracellular molecules (Tyr kinase Lyn) -augments signals delivered by the B cell receptor

Question 16

CR2

Answer 16

-interacts with C3d (formed by C3b cleavage by Factor I)

Question 17

CD22

Answer 17

-constitutively associated with BCR in resting B cells
-following B cell activation, delivers a negative signal
-due to the action of a tyrosine phosphatase (SHP-1) bound to ITIMs
ITIMs=immunoreceptor tyrosine-based inhibition motif

Question 18

B cell Coreceptor Signalling

Answer 18

-allows B cell activation to occur when fewer mIg molecules are engaged by antigen

Question 19

T Cell Anergy

Answer 19

• CD4+ or CD8+ T cells that receive a signal through the TCR/CD3 complex but fail to receive a costimulatory signal enter into a state of nonresponsiveness termed clonal anergy
• Anergic T cells are unable to respond to an antigenic peptide as a result of alterations in key components of TCR signalling pathways

Question 20

Peripheral T cell populations-gamma delta T cells

Answer 20

• most peripheral T cell express alpha-beta TCR
• small pop of double neg T cells express gamma-delta TCR
• not limited in activity by self MHC
• provides 1st line of defence- can respond directly to heat shock antigens and mediate cytotoxicity
• found in skin, intestinal epithelium, pulmonary epithelium

Question 21

Peripheral T cell populations-naive T cells

Answer 21

• Naïve T cells express low levels of CD44 and high levels of CD62L (L-selectin) and CCR7 –> homing to secondary lymphoid tissues and extravasation (move from blood and enter lymph nodes) from the circulation
• Without antigenic stimulation, naïve T cells live 5-7 weeks.
• A naïve T cell that recognizes antigen/MHC on a DC or target cell becomes activated and initiates a primary response
• Activated T cells enlarge into a blast cell and undergo repeated rounds of cell division, generating either effector cells or memory cells.

Question 22

Peripheral T cell populations-effector T cells

Answer 22

• Effector T cells live for days to weeks
• express high levels of adhesion molecules
• have different recirculation patterns compared to naïve T cells

Question 23

Central Memory T cells

Answer 23

• reside in and travel b/w secondary lymphoid tissues
• longer lived
• greater proliferative capacity

Question 24

Effector Memory T cells

Answer 24

• reside in and travel b/w tertiary lymphoid tissues

- ability to differentiate into effector T cells allows rapid response to reinfection