Chapter 8- Cell Mediated Immunity Flashcards
T-cell activation
Also called T-cell priming. It is the stimulation of mature naive T cells by an antigen, which is presented to them by professional antigen-presenting cells. It causes their proliferation and differentiation into effector T cells. T-cell activation is the first stage of a primary adaptive immune response
Activated CD8 cells
Always become cytotoxic T cells
Activated CD4 cells
Become effector cells- there are 5 different types
Where do adaptive immune responses occur?
The immune system captures some of the pathogen and sequesters it in secondary lymphoid tissue, which is dedicated to the generation of adaptive responses. These responses don’t just occur anywhere in the body. Myeloid dendritic cells are the main cells responsible for capturing the antigen at the site of infection and bringing it to the secondary lymphoid tissue (a draining lymph node)
How do dendritic cell functions change during the adaptive immune response?
Dendritic cells lose their capacity for phagocytosis and the processing of antigens when they move to secondary lymphoid tissues. There, they gain the ability to activate naive T cells
Immature dendritic cells
Dendritic cells that are present in peripheral tissues. They don’t express co-stimulatory molecules and don’t act as professional APCs to naive T cells. Dendritic cells mature once they are exposed to an antigen
Mature (activated) dendritic cells
Dendritic cells in secondary lymphoid tissues. They express co-stimulators and other cell-surface molecules that allow them to present antigens to naive T cells and activate them. Once the cells mature, their dendrites are highly elaborated, and they facilitate interactions with T cells in the cortex of the lymph node- this is where naive T cells congregate
Functions of macrophages in the lymph node
Macrophages are found in the cortex and medulla of the lymph node and complement dendritic cell functions. The macrophages extract pathogens and their breakdown products from the afferent lymph coming from the site of infection. They filter the lymph so the pathogens won’t leave the node through the efferent lymph and cause systemic infection
Which cells are responsible for activating CD4 and CD8 T cells?
CD8 cells can only be activated by dendritic cells. CD4 cells can be activated by dendritic cells or sometimes macrophages. Pathogens are presented to CD4 cells on MHC class 2 and presented to CD8 cells on MHC class 1
Micropinocytosis
A specific, receptor-mediated form of endocytosis conducted by dendritic cells. The cell internalizes small volumes of extracellular fluid and soluble macromolecules in membrane vesicles. Bacteria and viruses are captured using this mechanism so they can be processed in the lysosomes. Delivers the particles to MHC class 2
Macropinocytosis
The nonspecific endocytosis of larger volumes of extracellular fluid. Occurs in dendritic cells, used to capture pathogens that are not recognized by the endocytic receptors. Delivers the particles to MHC class 2
Pathways processing antigens delivered to MHC class 2
- Receptor-mediated endocytosis of bacteria
- Macropinocytosis of bacteria or viruses
Presented to CD4 cells
Pathways processing antigens delivered to MHC class 1
- Viral infection
- Cross-presentation of exogenous viral antigens
Presented to CD8 cells
Virus-infected dendritic cells
Viral proteins are processed in the cytosol and delivered to the endoplasmic reticulum, where they bind to MHC class 1. The MHC molecules are taken to the cell surface, where they are surveyed by the antigen receptors of CD8 T cells
Cross-presentation
Dendritic cells use the cross-presentation pathway to load MHC class 1 molecules with extracellular pathogen-derived peptides. Some peptides in the endosomes are transported into the cytosol and degraded to nonamers by the proteasome, then loaded on to MHC class 1. Peptide-MHC class 1 complexes are transported to the cell surface for presentation to naive CD8 T cells
Dendritic cell receptors
Toll-like receptors- signals from the toll-like receptors when they recognize a pathogen alter gene expression, leading to activation of the dendritic cell.
Effects of dendritic cell activation
Uptake, processing, and presentation of antigens to MHC molecules become more efficient. The receptor CCR7 also appears on the cell surface
CCR7
A cell surface receptor on dendritic cells, which CCL21 (a secondary lymphoid tissue cytokine) binds to. When the ligand and receptor interact, the pathogen-loaded dendritic cells leave the lymph and enter the tissue of the draining lymph node. The signals also cause the dendritic cells to mature and change their functions to present antigens to naive T cells
Expression of MHC molecules as dendritic cells mature
During maturation, the expression of MHC class 1 and class 2 increases, leading to an abundance of stable, long-lived peptide-MHC complexes on the dendritic cell surface
High endothelial venules (HEVs)
Specialized thin-walled capillaries in the lymph node. T cells enter the lymph node through the arterial blood. When T cells pass through an HEV, the T cells bind to the endothelial cells and then squeeze between them to leave the blood and enter the lymph node in the T-cell area
T-cell area
Also called the T-cell zone. It is the area where naive T cells enter the lymph node, in the outermost part of the cortex. The T-cell area is the part of secondary lymphoid tissue where the lymphocytes are predominantly T cells
What happens when naive T cells enter the lymph node?
The naive T cells encounter and interact with mature dendritic cells. The T-cell receptors probe the peptide-MHC complexes on the dendritic cell surface to find ones that contain a specific antigen. When the T cell antigen receptor binds to the peptide-MHC complex, the T cell is selected to be retained in the lymph node and is activated by the dendritic cell
Co-stimulatory signal
Any signal that is required for the activation of a naive lymphocyte in addition to the signal delivered via the antigen receptor (T cell with the peptide-MHC complex). The co-stimulatory signal is also necessary for the cell to survive and divide. It is delivered when CD28 on the T cell binds to the B7 molecule on the dendritic cell. In this context, B7 is a co-stimulator and CD28 acts as its co-stimulatory receptor
B7 and CD28 signaling
CD28 (on the T-cell) binds to B7 (on the dendritic cell). This allows the peptide-MHC complexes to engage both the T cell receptor and the co-receptor. The intracellular signals generated by the antigen receptor, co-receptor, and co-stimulatory receptor are necessary for the activation of the naive T-cell, as well as its proliferation and the differentiation of its progeny to become effector cells
CTLA4
An additional and complementary B7 receptor that is expressed when T cells are activated. CTLA4 is structurally similar to CD28 but it binds to B7 in a much stronger manner than CD28. When B7 interacts with CTLA4, it acts as a brake that inhibits both the activation and proliferation of T cells
What changes are observed in naive T cells when they differentiate into effector T cells? (4)
- Acquire ability to synthesize certain cytokines and
molecules to help eradicate different pathogens - Reduced requirement for co-stimulation
- Changes in adhesion molecules, chemokine receptors
- Also, increased expression of CTLA-4
Identification of TH1 and TH2 T cells
1986: Mosmann and Coffman observed that clones of helper T cells could be separated into
two classes based upon the cytokines they secreted. The subsets appeared to differ in the type of immune responses they produced
Which cytokines are secreted by TH1 cells?
IFN-γ, IL-2
Which cytokines are secreted by TH2 cells?
IL-4, IL-5, IL-6
TH1 cells
Produce immune responses against intracellular pathogens (bacteria, viruses)
TH2 cells
Produce immune responses against extracellular pathogens (worms, parasites)
Polarized T cell response
When the cytokines responsible for driving the differentiation of TH1 and TH2 cells are secreted, it results in positive reinforcement- causes the functional effector T cells to drive further differentiation of the same effector T cell type. This can cause rapid expansion of a population of pathogen-specific CD4 T cells, and either TH1 or TH2 cells become dominant. When this occurs, the T-cell response becomes polarized
Polarized TH1 response
TH1 cells are dominant- corresponds to cell-mediated immunity. IFN-γ and IL-12 are responsible for driving TH1 differentiation
Polarized TH2 response
When TH2 cells are dominant- corresponds to humoral immunity. IL-4 is responsible for driving TH2 differentiation
Leprosy
A disease caused by persistent infection of macrophages with the acid-fast bacterium Mycobacterium leprae. In leprosy patients, the effector CD4 T cell response becomes polarized toward either TH1 or TH2 cells- this determines how the disease will progress. Both forms are chronic infections where the immune system can’t eradicate the mycobacteria. Found in warm tropical countries
Tuberculoid leprosy
Occurs when the TH1 response is dominant. The cytokines made by TH1 cells help the infected macrophage to suppress the growth and dissemination of the bacteria, by forming granulomas around the bacteria. There is a chronic state of inflammation that damages the skin and peripheral nerves, but the disease progresses slowly and people don’t usually die from it. The organisms are present a low to undetectable levels in tissue and have low infectivity. Patients have normal serum immunoglobulin levels and normal T cell responsiveness
Lepromatous leprosy
Occurs when the TH2 response is dominant. Pathogen-specific antibodies are produced, but aren’t effective against the bacteria hidden in macrophages. When their proliferation is unchecked, the bacteria disseminate throughout the body. They disseminate into bone and cartilage, and cause nerve damage, tissue destruction and eventually death. Organisms show florid growth in macrophages and have high infectivity. Patients exhibit hypergammaglobulinemia and low or no T-cell responsiveness
TH1 cytokines in leprosy
TH1 cytokines characterize tuberculoid leprosy. In this form, the TH1 response is beneficial. There are few bacteria and little/no antibody. There is some nerve and skin damage, but slow disease progression.
TH2 cytokines in leprosy
TH2 cytokines characterize lepromatous leprosy. In this form, the TH2 response is ineffective. There is abundant bacterial growth and high levels of antibodies that are ineffective. There are gross levels of tissue destruction and the disease is fatal
Cross-regulation
Cytokines (IFN-γ and IL-4) both promote growth of the subset of T cells that produces them (TH1 or TH2) and then inhibits the development and activity of the opposite subset. Transcription factor expression also dictates subset commitment
T-bet
A transcription factor that drives naive T cells to become TH1 cells and suppresses TH2 differentiation. When the T cells are exposed to IFN-γ, T-bet is up regulated and GATA3 is down regulated
GATA-3
A transcription factor that drives cells to become TH2 cells and suppresses TH1 differentiation. When T cells are exposed to IL-4, GATA3 is up regulated and T-bet is down regulated
Positive and negative feedback to polarize CD4 T cell responses during leprosy
Transcription factors promote the genes necessary for the expression of TH1 and TH2 cytokines
Types of effector CD4 T cells (5)
- TH1
- TH2
- TH17
- TFH
- Treg
How are the types of CD4 effector T cells differentiated from each other? (4)
- Cytokines that induce their
differentiation (local environment) - Unique transcription factor
- Cytokines produced
- Role in immune response
TH17 cytokines that induce differentiation
IL-6, TGF-β, and IL-23
TFH cytokines that induce differentiation
IL-6 and IL-21
Treg cytokines that induce differentiation
TGF-β
TH17 transcription factors
RORγT turns on IL-17 gene expression in T cells. IL-17 then goes on to induce epithelial and stromal cells to secrete CXCL8, which is responsible for neutrophil recruitment and activation. Stat3 is also necessary for TH17 differentiation
TFH defining transcription factor
Bcl-6, which turns on CXCR5 gene expression in T cells. CXCL13 is found in the follicle, and CXCR5 acts as its receptor
Treg defining transcription factor
FoxP3, which turns on IL-10 and TGF-β expression in T cells
TH17 characteristic cytokines
IL-17 and IL-22
TFH defining cytokines
IL-21
Treg defining cytokines
TGF-β and IL-10
TH1 functions
IFN-γ activates macrophages and helps eradicate microbes (viral and intracellular bacterial infections) that
survive/replicate within macrophages. Especially ones that are able to evade
intracellular killing mechanisms (NADPH oxidase,
enzymes, etc.). TF1 cells also promote B-cell class switching to
opsonizing IgG antibodies. TH1 development is induced by IL-12 (DC) and IFN-γ (NK
cells) produced during an innate
response
TH2 functions (3)
Controls infections by extracellular parasites, promotes eosinophil and mast cell responses, promotes B-cell class switching to IgE antibodies. Secretes non-inflammatory cytokines. Development is induced by IL-4, secreted by either basophils or NK cells
TH1 transcription factors
T-bet turns ON IFN-γ gene expression in T cells
TH2 transcription factors
GATA3 turns ON IL-4 and IL-5 gene expression in T cells
TH17 functions (3)
- Development induced (by IL-16 and TGF-β) during extracellular bacterial and fungal infections
- Has a key role in maintaining mucosal barriers
- Enhances the neutrophil response
TFH cell functions
Follicular helper cells- they promote germinal center responses. Promote B cell class switching to the appropriate isotype, depending on the infection type. They also activate B cells to refine the antibody response- trigger naive B cell activation and differentiation into plasma cells
Treg cell functions (3)
- Regulatory helper cells, development is induced by TGF-β and the absence of IL-6
- Suppress other T cell responses to limit damage and promote healing
- Prevent autoimmunity- cytokine secretion, cell-cell contact, and cytolysis
Target cell
Any cell that is acted on directly by effector T cells. Effector CD4 T cells never directly attack the pathogens that cause infection, but they do help other cells to do this by forming a cognate pair with a target cell
Plasticity
CD4 effector T cells have a limited ability to transition from one subset to another. Properties can change with the local environment and the cytokines it contains. Could provide a potential avenue for immunotherapies
CD4 target cells
Interact with lymphocytes, phagocytes, and granulocytes
CD8 target cells
Interact with a wide range of target cells (essentially all cells in the body) although they are functionally homogenous. They provide a major defense against intracellular infections (mostly viral infections)
CD8 activation
CD8 cells can be destructive, so their activation in secondary lymphoid tissues requires stronger co-stimulation than those needed for CD4 cells.
Ways to activate a naive T cell (2)
- A naive CD8 T cell can be activated directly by a virus-infected dendritic cell
- A dendritic cell or other cell with MHC class 2 molecules that induces insufficient co-stimulation can be helped by CD4 effector T cells to induce activation
Direct activation of naive CD8 cells
Naive CD8 cells recognize MHC class 1. Sometimes, the interaction of a virus-specific naive CD8 T cell with a dendritic cell displaying viral peptide-MHC class 1 surface complexes is enough to activate the cell. Signals from the T cell receptor and CD28 stimulate the naive CD8 cells to make IL-2 and a high affinity IL-2 receptor, which interact and cause the T cells to proliferate and differentiate. Clones of cytotoxic T cells are produced
Activation of CD8 cells using CD4 cells
In this situation, the dendritic cell presents virus-derived peptides to a CD4 effector cell.CD8 recognizes a viral peptide on MHC class 1, and CD4 recognizes a viral peptide on MHC class 2. IL-2 from the CD4 T cell drives the proliferation and differentiation of the virus-specific CD8 T cell to form T cell clones. There is a combination of intracellular signals generated by the IL-2 receptor, TCR, CD8 co-receptor, and CD28 co-stimulatory receptor that drives the proliferation of the CD8 cells
