Lesson #9: T-B Cooperation; co-stimulation: role of accessorial molecules; T-dependent and

independent responses; germinative centre reaction and isotypic switch. Cytokines and cytokine
receptors. Th1 and Th2 responses. Tolerance: recognition and discrimination between self and non-
self. Mechanisms of central (negative selection) and peripheral tolerance (anergy, deletion and
suppression).
Role of accessorial molecules (AM):

 BCRs and TCRs have short cytoplasmic tails with no signal transducing capability
 BCRs associated with Ig alpha and beta, TCRs associated with CD3 with ITAMs
CD3 (a gamma chain, delta chain and 2 epsilon) and 2 zeta chains
 AM have ITAMs which work with other tyrosine kinases; Scr: Fyn, LyK and Lyn; Syk: Zap70
(amplifier)
TCRs associates with LyK, CD3 associates with Fyn, Iga and Igb associates with Syk, Z-chain
associates with Zap70
Adaptor molecules and propagators:

 LAT – Linker for the Activation of T cells

 Grb2-SOS-RasGTP/GDP – MEKKK, MEKK, MEK – AP-1 (transcription factor)
 PLC-y acts on PIP2 leading to DAG/IP3 – IP3 increase in intracellular Ca2+ acts on calcineurin
freeing up NFAT (IL-2, IL-4, TNF)
 PKC phosphorylates Ik-B freeing NF-kB
Role of mitochondria:

 Generation of ROS specifically H2O2 vital for proper activation of transcription factors such as
NFAT.
 Also increase in TCA provides energy for proliferation and
Results of activation

 Clonal expansion
 Differentiation (Th0 to Th1, Th2, Treg, Th17
 Effector activities (cytokine production, cytotoxicity)

Co-stimulation
T-Cell and APC

 Co-stimulation necessary as absence could lead to anergy and/or apoptosis, antigen

independent
 Most studied is B7.1/2-CD28 co-stimulation (CD28 on T cell and B7 on APC), potentiates and
leads to full activation of T cell
 Co-stimulation leads to survival, proliferation and differentiation.
 Absence of B7 on APC signifies immature APC (absence of PAMPs), therefore T cell could be
reacting to self-antigen or molecule to be tolerated. Subsequent inactivation promotes Tcell
deletion or development of immune tolerance.
 CTLA and PD-1 are inhibitory (behind B7) usually found on Treg, antibodies can be produce
similar to CTLA – immunotherapy
 Licencing and 3rd signal, APC with minimal B7 expression partially activated Tcell with no
CD40L. Immune synapse leads to expression of CD40L in Tcell and subsequent synapse with
CD40. Further activation leads to expression of cytokine receptors on Tcell. Tcells license
APCs by encouraging higher expression of B7 and IL2 production.
  Turning off activation:
Inhibitory receptors (ITIMs) bind tyrosine phosphates eg, SHIP which removes phosphates
from PIP3
Ubiquitination of ZAP70 and zeta chains – degradation
B Cell activation and receptor

Tolerance