Lecture 9: Cell-Mediated Immune Responses Flashcards
Listeria
- example of microbe that survive within phagocytes.
- has ways or persisting inside phagolysosome for a long period of time.
Intracellular microbes replicate within the ______________, where they are protected from microbial activities.
cytoplasm of host cells
Many viruses enter host cells through cell surface __________.
receptors
________ lymphocytes destroy cells infected with microbes.
________ lymphocytes also help B cells produce antibodies.
CD8 T
CD4+ T
T Cell responses require interactions with other cells. What are some examples of these cells?
Infected host cell, Phagocyte, B cell
Why do T cells only respond to antigens presented by other cells?
T cells require peptides presented in the context of MHC molecules
What determines the type of T cell response induced by the antigen?
The involvement of CD4 or CD8 in TCR-MHC-peptide recognition
What are involved in the interaction of a T cell and infected host cell?
Class I MHC-peptide
TCR
CD8
What are involved in the interaction of a T cell and phagocyte?
Class II MHC-peptide
TCR
CD4
What are involved in the interaction of a T cell and B cell?
Class II MHC-peptide
TCR
CD4
The TCR complex results in
TCR complex results in an effective division of labor for TCR signaling
T cell signaling: TCR mediates signal 1
Steps
- TCR variable region detects antigenic peptide.
- The presenting MHC molecule directs the T cell response (cytotoxic versus T helper).
- Conserved CD3 and ζ complexes signal to the T cell.- Signal transduction
In T cell signaling, it is a conserved process when
There is antigen recognition
Detection of a bewildering array of ligands (antigenic peptides) can be converted into
A conserved series of T cell responses.
LFA-1
lymphocyte function antigen 1
- Major T cell integrin
- binds ICAM-1 on APCs
What is the purpose of integrins in T cell signaling?
T cells recognize antigens weakly. For a productive TCR response, the T cell-APC interaction must be stabilized the integrins.
ICAM-1
Intracellular adhesion molecule 1
- located on the APC
- where the LFA-1 binds
Adhesion molecules
assist in stabilizing the interaction between the APC and T cell such that the T cell receptor has a greater chance to recognize peptide MHC and the co-receptors.
How does adhesion works in T cell signaling?
- LFA-1is present in a low-affinity binding state on resting naive T cells.
- Exposure to chemokines converts LFA-1 (also shifts conformation) to a high affinity state that clusters within minutes.
- As a result, T cells bind APCs strongly in the cell interface of TCR-peptide-MHC contact.
- Thus, activation of the TCR complex is strengthened.
- TCR signaling further strengthens the affinity of LFA-1 for ICAM-1, thereby increasing the strength of T cell-APC interactions and further stabilizing T cell signaling.
T cell costimulator interaction and signaling: Signal 2
- Upon infection, APCs present microbial peptide antigens on MHC molecules.
- At the same time, microbial PAMPs stimulate expression of costimulators on APCs.
- T cells that respond to MHC-microbial antigen complexes also receive a second signal (i.e. B7) from the APC.
- The result is a fully active T cell that contributes to the anti-microbial immune response.
When you have an activated T cell, they can produce ___________ ( autocrine effect )
cytokines
Costimulatory signals
are required for optimal T cell activation and proliferation
What are the three signal hypothesis?
Signal 1
Signal 2
Signal 3
Signal 1
antigen-specific TCR engagement of MHC + peptide
Signal 2
contact with costimulatory ligands
Signal 3
- cytokines directing T cell differentiation into distinct effector cell types.
- activated APC
- not only you’re gonna have B7 upregulated, but you’re gonna have cytokines,
The combination of the three signals leads to
differentiation of the T cells
IL-12
- one of the cytokines produced in paracrine signaling
- have very specific effects on T cells
IL-2
- cytokine produced in autocrine signaling
- stimulates proliferation
TCR signaling results in changes in gene expression in _______.
The newly induced genes lead to differentiation of naive T cells intoo ________, ___________ or ____________.
T cells;
effector cells, cytotoxic CD8+ T cells or helper CD4+ T cells.
Differentiation
the process by which a cell becomes distinct or specialized, acquiring functionality lacking in naive cells.
Differentiation coincides with ________________ and leads to the generation of large numbers of differentiated effector cells.
clonal expansion
Why are there different pathways in differentiation?
When you need to deal with one particular kind of pathogen, like a virus, the kind of orchestration that CD4 cells will mediate to deal with a virus will be different than the kind of orchestration that the immune system needs to bind the CD4 cells.
You can have a more directed response based on the pathogen.
What are the two major differentiation pathways?
Type 1 response and Type 2 response
Type 1 response
- common in our modern times
- intracellular pathogens inducing cell-mediated immunity (most viruses, some bacteria and fungi)
IFN- γ
- extremely important for dealing with viruses.
- most important cytokine produced by type 1 helper cells
- tends to make B cell produce antibodies that are particularly good for opsonization (ex; IgG) and also for complement binding.
- potent activator of macrophages, thereby enhancing microbial killing.
T-Bet
strong inducer of IFN- γ
STAT4
upregulated by IL-12
regulates T-Bet
this signal is gonna drive the CD4 cell down to the TH1 pathway.
IL-12
In type 1 response, what gets produced and secreted by the dendritic cell? (TH1 polarizing factors)
IL-12
Type 2 response
pathogens inducing humoral immunity, particularly extracellular parasites(e.g., worms)
In type 2 response, what gets produced and secreted by the dendritic cell? (TH2 polarizing factors)
IL-4
STAT6
produces by IL-4
GATA-3
strong inducer or IL-4, IL-5, and IL-13
These cytokines are particularly important for dealing with worms (ex: they trigger most cells to attack the worms).
IL-4
IL-5
IL-13
CD4+ effector cells (activated CD4)
produce surface molecules and cytokines that mainly activate macrophages and B cells.
CD40L
active CD4+ T cells express the surface molecule CD40L
CD40L binds _______, on macrophages, B cells and dendritic cells.
When a macrophage is activated, it will express this molecule.
CD40
What happens when CD40L binds to CD40?
B cells and macrophages become activated
Dendritic cells increase expression of costimulators. What is the effect of this?
further activating CD4+ T cells
CD4+ T cells
differentiate into various types of helper cells.
The “double-whammy” approach of IFN- γ importance
greatly enhances digestion of microbes my macrophages.
CD8+ T cell differentiation TH1 support the activation and differentiation of
CD8+ cytotoxic T cells
How CD8+ T cell differentiation leads to the activation and differentiation of CD8+ cytotoxic T cells?
- Initially there is a proliferation (clonal expansion) of the activated cell to deal with the infection at hand (the effector cell population)
- As the infection is cleared, that population dies off, or differentiates into a smaller population of CD8+ memory cells.
CTLs (CD8 T cell)
kill up close, and personal, to prevent damage to non-target cells.
- can induce cell suicide with their target cells.
What happens during conjugate formation?
CD8 T cells binds to the target cell
What happens during the interaction of CTL and target cell?
- CD 8 T cells binds to the target cell (conjugate formation)- takes 1 min.
- CTL cytoplasmic rearrangement- reorientation of centrosome towards the target cell. (6 min.)
- CTL granule exocytosis (5-6 min)
4a. Apoptosis (~30-40 min)
or
4b. Dissociation then CTL recycling
What happens in the synapse between a CTL and a target cell?
perforin perforates the target cell membrane allowing apoptosis inducers inside.
What do you call the killer enzymes inside a granule?
Granzymes
What happens when perforin comes to the membrane?
It can form a pore on the target cell membrane. This presumably allows those granzymes into the cytosol of target cell. Once inside the target cell, then there’s all kinds of enzyme substrates for the granzymes inside the cell that will make it cleave, which starts the suicide cascade.
What is a perforin?
proteins
has a lot of subunits but identical to each other.
9 perforin molecules form a pore together through a _____________ process
self-assembly
T cell activation steps
- Activated T cells produce cytokines.
- Cytokines drive clonal expansion of stimulated T cells.
- Some activated T cells differentiate from naive to effector cells, destroying microbe infected cells.
- Others become memory T cells- functionally inactive, but very long-lived (months to years) and respond rapidly to the same microbe.
- Microbial destruction removes antigen, resulting in a decline of the population of the responding clone.
Steps in the interaction of CTL and target cell
- Ca2+ increase in CTL
- Killer enzymes (granzymes) inside the granule
- Granule that contains granzymes attaches to the membrane and releases the killer enzymes to the synapse between CTL and target cell.
- Perforin monomers attaches to the membrane of target cell.
- Polymerized perforin is formed
- Completed pore
T cells respond to antigens and costimulators with the production of ________.
cytokines
Cytokines are produced mainly by __________ and ___________
macrophages and T cells (especially CD4+ T cells)
Cytokine production is transient to regulate immune responses. Why you don’t want cytokines for years after an infection?
Because this could help drive autoimmunity or have your cells activated when they shouldn’t.
Cytokines act in ________ and ________ manners to stimulate multiple arms of the immune response.
paracrine (work on other cells) and autocrine (work on itself)
General properties of cytokines
- Produced transiently in response to antigen.
- usually acts on same cell that produces the cytokine (autocrine) or nearby cells (paracrine).
- Pleiotropism: each cytokine has multiple biologic actions.
- Redundancy: multiple cytokines may share the same or similar biologic activities.
T Cell responses- Cytokines
( graph of time vs. cell number)
- In the absence of antigen the number of antigen-specific T cells is very low.
- APCs present antigens to T cells.
- Cytokines and stimulation by APCs leads to a rapid increase in T cell numbers.
- T cells diminish microbial numbers.
- Declining microbial numbers= less Ag, costimulators and cytokines. As a consequence, T cell numbers drop.
The number of T cells specific for any given antigen is about ___________
1 in every million
T cell responses- Clonal Expansion
T cell activation results in clonal expansion of antigen-specific T cells. During expansion, only antigen specific T cells expand.
CD8+ T cells increase about 10,000- fold and CD4+ T cells increase about 100-1,000 fold. Why is this?
You need more soldiers than you need commanders.
Development of memory T cells
- a fraction of antigen-activated T lymphocytes persist as memory T cells after an infection has passed-some of them are effector cells.
- Memory T cells reside in lymphoid tissues, in mucosal barriers and in circulation.
- Memory T cells do not continue to produce cytokines or kill infected cells, but they may do so rapidly upon re-infection.
In the absence of microbial antigens, any peptide presented on an MHC molecule is likely a __________.
self-peptide
A TCR that recognizes such a MHC-peptide complex is _____________.
auto-reactive
In lack of costimulator signaling, the naive T cell does not receive a second signal and becomes ____________(stunned state). - critical protection against auto-reactive lymphocytes in periphery.
anergic
Barrier to generate T cell response:
T cells must encounter antigen.
What is a solution for this?
APCs concentrate antigens in the lymphoid organs.
Barrier to generate T cell response:
T cells must determine the appropriate response (CD4+ or CD8+)
What is the solution for this?
Class I and Class II MHC molecules direct the specificity of the response.
Barrier to generate T cell response:
T cells must encounter antigen long enough for T cell signaling to occur.
What is the solution for this?
Adhesion molecules tighten interactions between T cells and APCs
Barrier to generate T cell response:
The T cell response must be directed against microbial antigens and not harmless proteins.
What is the solution for this?
2nd signals ensures responses are elicited against microbial antigens.
Barrier to generate T cell response:
A small number of T cells have to mediate the initial response.
What is the solution for this?
Amplification mechanisms (clonal expansion, cytokine production, etc.) boost the T cell response.
