Transcript MICR 304 S2010 Lecture 11 T Ly - Cal State LA

MICR 304 Immunology &
Serology
Lecture 11
T Ly
Chapter 6.8,6.10,6.11,6.19,7.7-7.10,
7.13-7.22, 7.26, 7.29,8.4, 8.11-8.33
Fig. 6.18
Overview of Today’s Lecture
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Cell signaling through TCR
Development of T cells
Positive and negative selection
Survival and maturation in peripheral
lymphoid tissue
Key Players in Immunology
Innate
Adaptive
Cells
Phagocytes
Epithelial Cells
NK Cells
Lymphocytes
(B-Ly, T-Ly)
Effector Molecules
Complement
Antimicrobial
(Poly)Peptides
Antimicrobial
Lipids?
Antibodies
T-Lymphocyte Characteristics
• Originate in bone marrow
• Migrate to and mature in thymus
(thymocyte)
• Differentiation is mediated through
NOTCH1 receptor
• Antigen recognition through T-cell receptor
– Recognize digested antigen
– Recognize antigen presented on specialized Most T cells
molecules called MHC I and II
T Cell Receptor Complex
• TCR: antigen –
recognition proteins
• CD3, z: invariant
signaling proteins
containing ITAM motif
Activation of T Cell Receptor
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Not clear yet
Dimerizing of TCR?
Conformation change of TCR
Clustering of T cell co-receptor and
CD4?
• Formation of immunological synapse
Immunological Synapse
• Structure formed around the site
of contact between a T cell and
its antigen presenting cell
• TCR, co-receptor, and signaling
proteins concentrated at the
contact site
• Two zones
– Central supramolecular activation
complex (cSMAC)
• Signaling proteins
• CD28: costimulatory
• CD2: adhesion molecule
– Peripheral supramolecular
activation complex (pSMAC)
• LFA-1: Integrin
• Talin: cytoskeletal protein
Kiss of Death
Immunological synapse also plays a role in
secretion of cytokines and cytotoxic granules.
T Cell Activation through TCR
• Fyn and Lck
phosphorylate ITAMS
in T cell receptor
complex allowing Fyn
to bind ZAP-70.
• Subsequent signaling
is similar to B cell
signaling.
CD 28: Co-Stimulatory Receptor
for Naïve T Cells
• Important for stimulation of
naïve T cells
• CD28 expressed on naïve T
cells
• Binds to the co-stimulatory
ligands B7.1 (same as CD80)
and B7.2 (same as CD86).
• Expressed on specialized APC
like dendritic cells.
Simultaneous Activation of TCR and
Co-stimulatory Molecules is required
for T Cell Effector Response
Activated T Cells Secrete and
Respond to IL-2
MHC Molecule Participates in
Antigen Recognition
• Co-recognition of foreign peptides and MHC molecule
– Resulting from direct contact between TCR and MHC
– Indirect effect of MHC polymorphism on the peptides that
bind to MHC or on their bound conformation
Alloreactivity of T Cells
Normal
Antigen fits well
to TCR
Allogeneic MHC molecules
fits well to TCR
T Cell Development
Main Phases of a T Cell’s Life History
T cell precursor
Rearrangement of TCR genes in thymus
Immature T cell
Positive selection (+ self MHC)
Negative selection (+ self peptide)
Mature T cell
Migration to peripheral lymphoid organs
Activated T cell
Effector T cell
Memory T cell
Main Steps in T Cell Development
The Thymus
• Organ in upper anterior thorax above heart
• Consists of numerous lobules
– Outer cortex
– Inner Medulla
• Main cell types
– Network of epithelial cells (thymic stroma)
– Developing T-Cells
– Macrophages, dendritic cells
• Is developed at birth, greatest T-cell production by
puberty, then slow regression
• In mice secondary thymus-like tissue found in neck
How do we Know that T-cells
are Important in Immunity?
• Studies with mice
– Thymectomy at birth leads to
immunodeficiency
– Nude mice
• Gene defect: no thymus, immunodeficient and
hairless
• Human disease: DiGeorge’s Syndrome
– Lack of thymus associated with
immunodeficiency
Cellular Organization of the Thymus
Bone marrow precursor
Immature T-Cells
95% die
Mature naive T-Cells
Hassall’s corpuscle
(Cell destruction?)
Blood stream
Interaction of Thymocytes with
Epithelial Cells in Thymus
Thymocyte
Epithelial Cell
Removal of Dysfunctional Thymocytes
• Takes place mostly in thymic
cortex
• Thymocytes undergo
apoptosis
– Failure to interact with self
MHC molecules
– Strong response to self
peptides
• Apoptotic cells (red stain)
are rapidly phagocytosed by
macrophages (blue stain)
Marked Changes of Cell Surface Markers in
Developing Thymocytes
Positive/Negative
Selection
CD4 and CD8 Expression in
Developing T Cells
CD3+
CD4-/CD8-
CD3+
CD4-/CD8gd
CD3+
CD4+/CD8+
preab
CD3+
CD4+/CD8+
ab
CD3+
CD4+
ab
CD3+
CD8+
ab
Positive and Negative Selection of
Thymocytes
• Double positive thymocytes have a life span
of 3 to 4 days and are programmed to enter
apoptosis if not rescued.
• Developing thymocytes are exposed to self
peptide presented on self MHC molecules
• They are rescued from apoptosis if their TCR
recognizes self-peptide on self MHC
molecules.
• However, if their TCR responds too strongly
to self peptide on self MHC molecules, they
are sent to apoptosis.
Tissue Specific Protein Expression
in the Thymus
• Specialized stromal
cells in the thymic
medulla express so
called tissue specific
proteins.
• The expression of
such genes is
controlled by AIRE
(autoimmune
regulator)
Green: AIRE
Red: thymic medullary epithelial marker
Effector T Cells
Effector T Cells
Cell Type
CD
MHC
Effect
T Helper cells
CD4
MHC II
Cytokine production
Augmentation of immune
response
Cytotoxic T cells
CD8
MHC I
Release of cytotoxic
granules
Apoptosis
Regulatory T cells
CD4
MHC II
Cytokine production
Inhibitory cytokines
The Various Effector T cells and
Their Role in Host Defense
Activate
epithelial
cells
Effector Molecules of
Activated Effector Cells
Cytotoxicity
Macrophage
enhancement
Allergy
Neutrophil
recruitment
Epithelial cell
activation
Down
regulation of
immune
response
Well Defined T Cell Derived Cytokine (1)
Well Defined T Cell Derived Cytokine (2)
Activation of Naïve T Cells by
Dendritic Cells
Refresher: Antigen Presenting Cells
APC Derived Cytokines Influence
the Differentiation of TH Cells
Differentiation of TH Cells
Today’s Take Home Message/Active
Learning Exercise
• Complete the figure by adding all relevant cytokines including signal 3.