lymphocyte activation

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POSTGRADUATE
SCHOOL OF MEDICINE
LYMPHOCYTE ACTIVATION
David Lowe
MDSC175: Transplantation Science for Transplant
Clinicians (Online)
A MEMBER OF THE RUSSELL GROUP
CONTINUING PROFESSIONAL DEVELOPMENT
Lymphocyte Activation
Lymphocyte Activation
T-cell APC interaction
Co-stimulation
Early T-cell signaling
Downstream events of TCR
signaling
B-cell Response
Mechanisms of B-cell
activation
2
Lymphocyte Activation
T-Cell APC Interaction
3
Lymphocyte Activation
Naïve Lymphocyte Activation
Signal 1: low affinity TCR-MHC plus
peptide interaction
Signal 2: mediated by interaction
between CD28 and B7 (CD80/86)
Important: Once activated, T cells are able to proliferate in response
to a single signal
4
Lymphocyte Activation
TCR/CD3 Co-receptor Complex
• Thought to comprise one submit
each of CD3γand δ and two
subunits of CD3ε
• Two disulphide linked ζ subunits
• All subunits contain ITAMs which
can become phosphorylated by
kinases which are activated upon
TCR MHC interaction
5
Lymphocyte Activation
6
Early T-cell signaling events
•
Protein Tyrosine Phosphorylation
•
Requires CD4/8 interaction
•
CD4/8 express Lck, a protein tyrosine kinase (PTK)
•
PTKs can phosphorylate ITAMs found within the TCR complex
•
Recruitment of Zap-70 and subsequent phosphorylation by Lck
Lymphocyte Activation
Moving on to Downstream Events
7
Lymphocyte Activation
TCR Signaling: Ras/MAPK Pathway
8
Lymphocyte Activation
9
TCR Signaling: Phosphotidylinositol pathway
Lymphocyte Activation
10
TCR Signaling: Phosphotidylinositol pathway
Lymphocyte Activation
B Lymphocyte Activation
11
Lymphocyte Activation
B Cell Co-stimulation (1)
12
Lymphocyte Activation
B Cell Co-stimulation (2)
Internalisation of BCR
following direct
binding to antigen
leading to
presentation in
context of class II MHC
molecule
13
Lymphocyte Activation
14
References
• Alberts et al, Molecular Biology of the Cell. 4th edition, New York: Garland
Science; 2002
• Shipkova and Wieland, (2012) Surface markers of lymphocyte activation and
markers of cell proliferation, Clinica Chimica Acta, 413, 1338–1349
• Veillette and Davidson (2014) Immunology: When lymphocytes run out of
steam, Nature, 510, 222–223
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A MEMBER OF THE RUSSELL GROUP
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