Aims
• Describe T cell maturation and be able to
differentiate naïve and effector T cells.
• Differentiate the development and functions of Th1
and Th2 cells.
• Describe the mechanism of T cell cytotoxicity.
• Readings: Abbas & Lichtman, Chapters 4, 5 & 6
T Cell Maturation and Selection
• Occurs in the thymus.
• Positive selection
– T cells must recognize a MHC
molecule in order to survive.
– Makes sure TCR molecule can
recognize MHC + peptide.
• Failure of positive selection
– No recognition of MHC+
peptide.
• Negative selection
– T cells who strongly recognize a
MHC molecule undergo
apoptosis.
– Eliminates self protein reacting
T cells.
Adapted from Abbas & Lichtman’s Basic Immunology 4-13
Intracellular Microbes
• Cell mediated immunity is responsible for intracellular
microbial infections.
• Common intracellular infections
– Phagocytosed microbe that survive in phagolysosomes.
– Microbe that escapes into cytoplasm.
Abbas & Lichtman’s Basic Immunology 5-1A
Intracellular Microbes
• Microbes that bind to membrane receptors and enter a
cell’s cytoplasm in order to infect a cell.
Abbas & Lichtman’s Basic Immunology 5-1B
Activation of T Cells
• Antigen
recognition
– MHC-TCR
• Activation
– Cytokines
• Clonal
expansion
• Differentiation
– CD4+, CD8+
Cytokines
Cytokines
Peripheral
• Effector function
Adapted from Abbas & Lichtman’s Basic Immunology 5-2
MHC-TCR Interaction
• TCR recognizes antigen (peptide) within MHC
molecules.
• CD4 binds to MHC class II molecules (CD8 to class I).
• Signaling begins with phosphorylation of the ζζ
associated with _CD3_.
Abbas & Lichtman’s Basic Immunology 5-4
CD4+ T Cell Activation
• Activation requires
two signals.
– 1) MHC/peptide
antigen binding to
TCR.
– 2) Costimulatory
molecule on APC
binding to specific
receptors on T cell.
• B7-1 (CD80) or B72 (CD86) on APC
binding to CD28 on
T cell.
Adapted from Abbas & Lichtman’s Basic Immunology 5-6
CD4+ T Cell Activation
• Activated T cells
produce cytokines
and cytokine
receptors.
– IL-2
– High affinity IL-2
receptor.
• Resulting in clonal
proliferation and
differentiation of that
T cell.
Adapted from Abbas & Lichtman’s Basic Immunology 5-6
CD4+ T Cell Activation
• If no costimulation
occurs when TCR binds
to MHC / Peptide, T cell
becomes nonresponsive
(anergy) or undergo
apoptosis.
• Only activated APCs
express costimulatory
molecules.
– Thus only naïve T cells in
direct contact with APC
containing microbial
antigen will be activated.
Adapted from Abbas & Lichtman’s Basic Immunology 5-6
CD8+ T Cell Activation
• Antigen presentation by
APC via MHC class I
(infected APC).
10,000 fold
– APC express costimulator
molecules.
• Phagocytosed infected cell
by APC results in antigen
presentation via MHC class
II to CD4+ T cell and MHC
class I to CD8+ T cell.
– CD4+ T cells secrete cytokines
to activate CD8+ T cells.
Adapted from Abbas & Lichtman’s Basic Immunology 5-7
Effector Function of CD4+ T Cells
•Differentiated effector cells appear 3-4 days after exposure to microbe.
• Activation of macrophages.
–
–
–
–
Expression of CD40L by CD4+ T cells.
CD40L bind to CD40 on Macrophages.
Secretion of cytokines (IFNg) by CD4+ T cells.
Results in macrophage killing of phagocytosed microbe.
Abbas & Lichtman’s Basic Immunology 5-10B
Effector Function of CD4+ T Cells
• Activation of a B cell.
–
–
–
–
Expression of CD40L by CD4+ T cells.
CD40L bind to CD40 on B cells.
Secretion of cytokines (IL-4) by CD4+ T cells.
Results in B cell secretion of antibody.
Abbas & Lichtman’s Basic Immunology 5-10B
Function of Th1 CD4+ T Cells
• Macrophages and dendritic cells
respond to bacterial or viral
infections by secreting _IL-12_
which causes naïve CD4+ T cells to
differentiate into Th1 cells.
Adapted from Abbas & Lichtman’s Basic Immunology 5-11A
IL-12
Function of Th1 CD4+ T Cells
• Th1 cells secrete IFNg.
– Macrophage activation.
• Stimulates expression of MHC
class II.
• Stimulates the expression of B7
costimulators.
– B cell production of IgG
subclasses involved in
phagocytosis via Fc receptors.
Adapted from Abbas & Lichtman’s Basic Immunology 5-11A
IL-12
Function of Th2 CD4+ T Cells
• If there is no
production of IL-12 by
the APC then the T
cell itself secretes IL-4
inducing its
differentiation into the
Th2 phenotype.
– This is what happens in
infections by helminths
which are too big to be
phagocytosed.
Abbas & Lichtman’s Basic Immunology 5-11B
Function of Th2 CD4+ T Cells
• Th2 cells secrete IL-4
– Stimulates the
production of (class
switch to) IgE by B
cells.
• Th2 cells secrete IL-5
– Activates eosinophils.
• Th2 cytokines (IL-4)
inhibit macrophage
activation and Th1
mediated immunity.
Abbas & Lichtman’s Basic Immunology 5-11B
Effector Function of CD8+ Cytotoxic
T Lymphocytes
• CD8+ cytotoxic T
lymphocytes recognize
MHC class I with peptides
on infected cells.
• Differentiated cytotoxic T
lymphocytes do not require
costimulation or T cell help
for activation.
Abbas & Lichtman’s Basic Immunology 6-10
Effector Function of CD8+ Cytotoxic
T Lymphocytes
• Cytotoxic T lymphocytes
kill target cells by releasing
granule contents.
– Perforin polymerizes resulting
in pores in target cell
membranes.
– Granzymes enter target cell
through perforin pores and
activate caspases resulting in
apoptosis.
Abbas & Lichtman’s Basic Immunology 6-10
Resistance to Cell-Mediated Immunity
• Inhibition of phagolysosome fusion.
• Mycobacteria escapes death by avoiding enzymes in
lysosome.
Abbas & Lichtman’s Basic Immunology 6-12
Resistance to Cell-Mediated Immunity
• Inhibition of class I MHC expression.
– CMV & EBV Inhibit proteosomal activity.
– HSV Inhibits transport of peptides into ER.
– CMV Removes class I MHC from ER.
Abbas & Lichtman’s Basic Immunology 6-12
Resistance to Cell-Mediated Immunity
• Production of inhibitory cytokines
– EBV secretes IL-10 (similar to IL-4) that inhibits
macrophage activation.
Abbas & Lichtman’s Basic Immunology 6-12
Resistance to Cell-Mediated Immunity
• Production of soluble cytokine receptors.
– Quench cytokines resulting in lack of cytokine activity.
– Pox virus secretes soluble IL-1 and TNF receptors.
Abbas & Lichtman’s Basic Immunology 6-12
Next Time
• Describe the humoral immune response.
• Compare and contrast the primary and
secondary antibody responses.
• Compare and contrast T-dependent and Tindependent antigens and the antibody response
to each.
• Describe effector functions of antibodies
including neutralization and ADCC.
• Readings: Abbas & Lichtman, Chapters 7 & 8
Objectives
1. Describe T cell maturation and be able to
differentiate naïve and effector T cells.
2. Describe the process of T cell activation
3. Describe the development and functions of
Th1 and Th2 cells.
4. Describe the mechanism of T cell cytotoxicity.