Lecture 11-Activation of naïve T cells Naïve T cells are activated in lymph nodes and spleen....
-
Upload
virginia-shepherd -
Category
Documents
-
view
220 -
download
1
Transcript of Lecture 11-Activation of naïve T cells Naïve T cells are activated in lymph nodes and spleen....
Lecture 11-Activation of naïve T cells
• Naïve T cells are activated in lymph nodes and spleen.• Dendritic cells are key antigen presenting cells for naïve T
cells.• Naïve T cells require MHC/peptide plus antigen-presenting
cell "costimulation" in the form of B7 molecules.• Only "professional" antigen presenting cells express B7
molecules. And these only express B7 when activated.• Antigen stimulation without costimulation can lead to loss
of T cell responsiveness and immune tolerance.
Reading Chapter 6
How naïve, mature T cells find antigen
• Antigen transport. Naïve cells are mainly in lymph nodes and spleen. Dendritic cells transport antigen to draining lymph nodes, blood borne antigens lodge in spleen.
• T cell entry to lymph nodes. T cells recirculate through lymph nodes using homing receptors, integrins and responding to chemokines constitutively produced by the lymph node stroma. (Parham 6.2-6.3)
• T cell scan of APCs. T cells scan antigen presenting cells. Interaction is initiated by adhesion molecules. (Parham 6.4)
• Antigen recognition.
Recognition by T cells of peptide/MHC on dendritic cell leads to stronger adhesion and a more prolonged interaction.
CD8killer
CD8 CD4
CD4Th1
CD4Th2
naive
effectors
Activation, proliferation, differentiation
Diverse outcomes of immune activation of mature T cells
Th1 vs Th2 is defined by distinctive pattern of cytokine expression
1 1
2
inappropriateactivation
leads to cell inactivation
inappropriateactivation
leads to cell inactivation
CD8 CD4
How are these cell fate decisions made?
T cells encountering antigen on non-activated professional antigen presenting cells become inactivated
inactivated
Appropriate activation of naïve T cells requires in addition to a ligand for the T cell receptor a second interaction with CD28. This second signal is called "costimulation." Under many conditions, dendritic cells provide this signal during a primary response.
Costimulation by signaling through CD28
• It is currently believed that naïve T cells require activation by dendritic cells, macrophages or other "professional" antigen presenting cells.
• Dendritic cells are most efficient because they not only take up and present antigen, but also because they move efficiently to lymph nodes to encounter naïve T cells.
• These professional antigen presenting cells provide peptide MHC complexes along with a critical "costimulation."
• Costimulation is believed to be a crucial interaction between the innate and adaptive immune systems that regulates T cell responses.
Special importance of dendritic cells in activating naïve T cells
Figure 6-2Immature
dendritic cells in tissues actively capture, take
up, and process antigens.
Upon maturation,
they migrate to draining lymph
nodes and present
antigens to T cells.
Green, MHC
Red, Lysosomes
Only activated antigen presenting cells
express B7 molecules which are among the
most important costimulatory signals.
Adjuvant: important component of vaccines
Ovalbumin
Ovalbumin+ Adjuvant
No detectable antibody response
Strong antibody response
Adjuvants work by slowing the release of antigen, promoting phagocytosis, and providing inflammatory signals that promote costimulation
Diptheria/ tetanus/ pertussis vaccine
Mixture of diptheria toxin (a soluble protein) tetanus toxin (another soluble protein) and killed Bordetella pertussis bacteria. The presence of the bacteria stimulates an improved response to the toxins (presumably by upregulating B7 expression by antigen presenting cells). It also leads to more inflammation and discomfort at the site of injection.
Current adjuvant research is trying to identify ways of improving the efficacy of vaccine adjuvants while at the same time reducing unwanted side effects.
Cross presentation for CD8 priming
•Problem: how can naïve CD8 cells get activated if activation requires peptide/MHC class I plus costimulation?
This would require that professional antigen presenting cells get infected with virus, for example.
•A second problem is that viruses that manage to suppress MHC class I would evade detection.
•Cross presentation of exogenous proteins on MHC class I can be specifically carried out by dendritic cells.
There is an important exception to the notion that class I MHC molecules present peptides generated within the cytoplasm.
What if the virus doesn’t infect macrophages or dendritic cells? How do viral peptides get presented by professional antigen presenting cells so that an immune response can be induced?
The answer is that dendritic cells, but not other cells, have a specialized mechanism for shuttling peptides taken up by endocytosis or phagocytosis into the MHC class I pathway.
Dendritic cell "cross presentation" of ingested antigens on MHC class I
Cross presentation = Dendritic cell, but not other cells, can take up antigens and shuttle them into the class I pathway.
This is most efficient when the antigens are particulate
Provides a mechanism to get viral and bacterial antigens into profession antigen presenting cells.
This induces an immune response to the offending pathogens.
Trends in Immunology
22:141-148 (2001)
Note that in almost all cases, two (or more) distinct cell types must be independently activated in order for a productive immune response to occur. In all cases, both innate and
antigen-specific stimulus is required.
CD4
CD8
CD8
B
1) Antigen specific2) Innate signals
1) Antigen specific2) Innate signals
1) Antigen specific2) Antigen specific
1) Antigen specific2) Antigen specific
1) Ag+MHC Class II2) B7 coexpressed by APC
1) Ag+MHC Class I2) B7 coexpressed by APC
1) Ag+MHC Class I2) CD4 effector Ag+MHC Class II
1) Ag:sIg crosslinking2) CD4 effector Ag+MHC Class II
Failsafe
Manipulation of costimulation for therapy
Tumor immunityTumors typically express MHC class I molecules, but fail to provoke an immune response because of CD4 or CD8 T cell tolerance. Some tumors do express unique antigens (such as mutated oncogenes) that could be used to direct killer T cells, but they fail to express costimulatory molecules.
Approaches•Force expression of B7 molecules in antigen tumor cells by gene therapy.•Immunize patients with their own tumors in the presence of powerful adjuvants.
B7
Concepts
• Naïve T cells encounter antigen in the draining lymph nodes and spleen, not at the site of infection.
• Antigen encounter involves transport of antigen, often by uptake of dendritic cells followed by their migration.
• Dendritic cells are key antigen presenting cells for naïve T cells. Other important professional antigen presenting cells are macrophages and B cells.
• Naïve T cells require peptide/MHC plus costimulation.• A major source of costimulation is B7 expressed by activated
professional antigen presenting cells.• B7 expression by dendritic cells and macrophages is often
stimulated by innate immune ligands.• Encounter of antigen in the absence of costimulation leads to
tolerance. And this is a major pathway of self-tolerance to peripheral antigens.
• Crosspresentation of exogenous antigens on MHC class I molecules is carried out by dendritic cells, but no other cells.
• Inducing costimulation is an important aspect of vaccine adjuvants.