T Cell (and B cell) Activation and Signalling Flashcards
T cells need 3 signal for activation
- TCR signalling
- Co-stimulatory signalling
- Cytokine signalling (autocrine and paracrine)
CD4 T helper cells interact w/ antigenic peptide via…
-class II MHC on APC
CD8 cytotoxic T cells interact w/ antigenic peptide via…
-class I MHC on target cell
Immediate, early, late genes in T cell activation
- 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)
IL-2R and IL-2 expression
-allows autocrine T cell growth, cell cycle progression and differentiation into memory cells and effector cells
TCR/CD3 Complex signalling- Major events
- 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
What is involved in signal transduction that leads to T cell activation
- TCR/CD3 complex
- CD4/CD8 co-receptors
- accessory molecules (e.g. CD2, CD28, CD45)
TCR/CD3 Complex signalling-CD45
-cell surface phosphatase that catalyzes the dephosphorylation of an inhibitory Tyr residue on p56lck (and p59fyn)
TCR/CD3 Complex signalling-calcium
- 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
Immunological Synapse
-TCR/CD3 complex molecules on the inside and adhesion molecules on the outside of the ring
Positive Costimulatory Signalling
- 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
Negatively Costimulatory Signalling
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
CTLA4 induction
- induced within 24h of TCR engagement
- out-competes CD28 for B7 molecules because of its higher affinity for these molecules
Complex of 3 proteins making up B cell coreceptor
CD19
CR2
TAPA-1
CD19
-has a long cytoplasmic tail that contain docking sites for intracellular molecules (Tyr kinase Lyn) -augments signals delivered by the B cell receptor
CR2
-interacts with C3d (formed by C3b cleavage by Factor I)
CD22
-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
B cell Coreceptor Signalling
-allows B cell activation to occur when fewer mIg molecules are engaged by antigen
T Cell Anergy
- 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
Peripheral T cell populations-gamma delta T cells
- 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
Peripheral T cell populations-naive T cells
- 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.
Peripheral T cell populations-effector T cells
- Effector T cells live for days to weeks
- express high levels of adhesion molecules
- have different recirculation patterns compared to naïve T cells
Central Memory T cells
- reside in and travel b/w secondary lymphoid tissues
- longer lived
- greater proliferative capacity
Effector Memory T cells
- reside in and travel b/w tertiary lymphoid tissues
- ability to differentiate into effector T cells allows rapid response to reinfection
