Lecture 7 - Adaptive Immunity: Lymphocyte Activation Flashcards
How does a naive CD4 T cell get activated during infection?
Integration of both Innate and Adaptive Immunity
Adaptive Immunity
- DCs phagocytose microbe and migrate to lymph node to present to CD4 T Cell w/ MHC II
- This is how the CD4 T cell knows the antigen is foreign
Innate Immunity
- Innate immune cells recognize PAMPs on the pathogen and release cytokines
- Cytokine receptors on Naive CD4 T cell bind cytokines
- This is how CD4 T cell knows the pathogen is harmful
Go through the steps of Naive CD4/CD8 T Cell activation?
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Antigen Recognition: APC presents to T cell w/ specific receptor for its antigen
- APC uses MHC I for Endogenous w/ CD8 co receptor and MHC II for Exogneous w/ CD4 co receptor - Activation of the T cell through autocrine/paracrine cytokine stimulation
- Clonal Expansion: rapid mitosis of T cell
- Differentiation of the two T cell type, TH and TC
- Effector Response: TH directs other immune cells and TC kills infected cells
- Memory: After infection over, effector cells apoptosed and CD4/CD8 memory T cells stored to speed up response 2nd time around
What are the types of effector functions for Mature Naive CD4/CD8 T cells?
Mature Naive CD4 T Cell
-Effector CD4 T Cell (TH): activation of macrophages, B cells, other immune cells
Mature Naive CD8 T Cell
-Effector CD8 T Cell (TC): Killing of infected “target cells” and macrophage activation
What are the interactions between T cells and APCs?
T cell__APC__Function
TCR MHC + Antigen Antigen Recognition
CD4/CD8 Coreceptor MHC I or MHC II MHC Specificity
CD28 B7 Positive co-stimulation
What do the various receptors on the T Cell (TCR, CD4/8, CD28) do when they bind the APC?
Produce intracellular signals that stimulate activation of the T cell
-Differentiation + Mitosis
What is the co-stimulatory receptor?
When APCs present antigens to T Cell:
- B7 on the APC binds to CD28 on the T Cell
- stimulates intracellular response
What is the CD3 Complex?
Stabilizes TCR in membrane and mediates the intracellular signalling from TCR/Co-receptor w/ MHC complex
What signals do T Cells require in order to reach threshold and induce activation?
1. TCR Signalling
- MHC-Antigen Complex / TCR-CD4
- Tells T Cell that antigen is nonself
2. Costimulatory interaction
- B7/CD28
- Only expressed when inflammation present
- PRRs on innate immune cells bind to PAMPs on pathogens and release pro-inflammatory cytokines to induce inflammation
- How T Cell knows antigen is harmful
3. Cytokine Signaling
- Cytokines/Receptors
- Autocrine self stimulation and paracrine signalling from APC and other innate immune cells
- How T Cell knows what kind of T cell to differentiate into
How does a T Cell know food is nonself but nonharmful?
Food don’t have PAMPs⇒No binding to PRR = No Inflammation
- No inflammation = no B7 costimulatory molecule expression
- No B7 = No costimulation = No Cytokine signalling
This is an example of further development of tolerance
-tolerance to nonself and nonharmful
What would happen to a T cell that binds a food antigen?
Binding of the MHC-Antigen Complex / TCR-CD4 without activation due to no inflammation generates intracellular signalling that leads to:
- Apoptosis of the T Cell
- The T Cell become anergic (cannot become activated)
- Some of those T Cells become TREG cells that will recognize this food in the future and inhibit further immune responses
What interleukins (cytokines) stimulate clonal expansion?
Autocrine activation with IL-2 and IL-2R stimulates mitosis
- This expands only population that has TCR that recognizes the antigen of interest
- Next step is differentiation
What influences T Cells to differentiate into the different TH subtypes?
PRRs on Innate Immune Cells bind PAMPs on the pathogen
- they release polarizing cytokines
- these cytokines tell the T Cell what kind of TH Cell is needed to fight this type of pathogen
What are the types of TH Cells?
TH1
TH2
TH17
TREG
TFH
What is the job of a Helper T Cell?
Coordinates other immune cells to help fight infection by using cytokines
- Type of TH cell influences the types of cytokines it releases
- The type of cytokines the TH cell releases determines the type of immune cells it recruits to fight infection
How does a TH1 Cell fight infection?
Cytokines Produced
- IFNγ = B Cell and Macrophage (Extracellular)
- IFNγ + IL-2 = NK and CD8 T Cells (Intracellular)
Types of Cells Affected
- B Cell → Plasma Cell → IgG
- Macrophage → Activated (better eater) macrophage
- NK / CD8 T Cell → Kill infected Cells
Kinds of Pathogens it Fights
- Combats both intra/extracellular pathogens
- Good for viral response or bacterial infection
What is different about the B Cells that are activated by TH1 vs TH2 Cells?
The B Cells that are activated by TH1 and TH2 Cells undergo:
- BOTH undergo clonal expansion then differentiation into Plasma Cells
- The Plasma cells activated by TH1 cells produce IgG antibodies
- The Plasma cells activated by TH2 cells produce IgA and IgE antibodies
What is different about IgG, IgE and IgA antibodies?
IgG
- Extracellular pathogen
- Opsonizes (coats) Ag w/ IgG antibodies making it harder to stick to surface
- Opsonization flags the pathogen for phagocytosis by macrophages
IgE
- Binds to cells that release inflammatory cytokines (MAST cells)
- When IgE receptors bind antigen it causes inflammatory cell to release histamine
- Inflammatory resposne
IgA
- Mucosal antibody
- Opsonizes the pathogen for later phagocytosis or mechanical expulsion
During primary exposure to a pathogenic microbe, what is the role of innate immune cells?
- trigger the inflammatory response to recruit immune cells
- eliminate microbes by phagocytosis and antimicrobial proteins
- limit growth and spread of microbes with antimicrobial proteins
- activate adaptive immunity with antigen presentation and cytokine
When professional APCs present antigens to mature naive T cells, intracellular signals cause the antigen-specific T cells to undergo rounds of mitosis. This is called….
clonal expansion
When naive T cells are activated, they secrete a cytokine called interleukin-2 (IL-2). IL-2 binds to receptors (IL-2R) on the T cell, which stimulates the secretion of more IL-2 and an increased expression of IL-2R. What type of signalling is responsible for this positive-feedback loop that leads to proliferation of activated T cells?
autocrine
What is the ligand on the APC that binds to each of the following T cell receptor molecules?
- CD28
- CD4
- CD8
- TCR
- CD28 = B7
- CD4 = MHC II
- CD8 = MHC I
- TCR = Peptide Antigen + MHC
In response to inflammation, professional APCs express a co-stimulatory molecule called (FILL-IN-THE-BLANK) that binds to the CD28 molecule on T cells during antigen presentation.
B7
Compare and contrast an effector lymphocyte and a memory lymphocyte.
Effector lymphocytes are used for the immediate defense against foreign microbes. Once the infection has cleared, the body apoptoses these effector cells.
Memory Lymphocytes are generated following encounters with an antigen and are characteristically long lived and more easily stimulated than naïve lymphocytes in order to mediate a secondary response to subsequent encounters with the same antigen.
How does a TH2 Cell fight infection?
Cytokines Produced
- IL-5
Types of Cells Affected
- B Cell → Plasma Cell → IgE and IgA
- Macrophage → Alternatively activated (inflammatory) macrophage
- Eosinophil and Basophils/MAST cells → Inflammation
Kinds of Pathogens it Fights
- Parasites
How does TH17 fight infections?
Cytokines Produced
- IL-17
Cells Affected
- Indirectly affects neutrophils
- Stimulates stromal and endothelial cells to release cytokines that recruit neutrophils
Types of Infection it Fights
- Bacterial and fungal infections
What are the effects of TH1 cell differentiation?
What are the effects of TH2 cell differentiation?
What are the effects of TH17 cell differentiation?
A 2013 study by Warfel et al. demonstrated that the acellular pertussis vaccine protects against disease but not infection and transmission (in an animal model). Why is this distinction important to understand in regards to vaccine effectiveness?
In animal models, they showed that the severe symptoms did not present, although there was colonization of B.pertussis. This is important because while symptoms in vaccinated individuals are not expressed, the colonization of these cells will decrease herd immunity because it can still be spread to vulnerable members f the population.
Warfel et al. studied immune responses (Fig. 5) in animals vaccinated with acellular vaccine (aP), whole cell vaccine (wP), and animals who had never been infected or vaccinated (naive). They also looked at convalescent (conv.) animals. What does convalescent mean?
infected with pertussis but now recovered
In figure 5 of the Warfel et al. 2013 paper, they describe measurements of three cytokines - interleukin-5, interleukin-17 and interferon-gamma - when studying immune responses in animals. Why did they look at CD4+ cells for the production of these cytokines?
They are helper T cells that produce these cytokines
In figure 5 of the Warfel et al. 2013 paper, they describe measurements of three cytokines - interleukin-5, interleukin-17 and interferon-gamma - when studying immune responses in animals. Match the cytokine with the cell type from which it is produced.
IL-5 ⇒ TH2
IL-17 ⇒ TH17
IFN-Y ⇒ TH1
In the absence of inflammation, what is the fate of a mature naive CD4 T cell if a DC presents nonself antigen with MHC II?
It differentiates into a regulatory T cell (T-REG) or It dies or becomes anergic
Polarizing cytokines influence the the type of T helper response (e.g. TH1 vs. TH2) created by CD4 T cell activation. What causes polarizing cytokines to be secreted by immune cells?
PAMPs from microbes bind to PRRs on immune cells
Based on experimental evidence of T helper responses (Warfel et al. 2013, Fig. 5; asterisks denote statistically significant differences between negative control and experimental group), what is the polarized response produced by convalescent animals (i.e. those infected with pertussis, survived and recovered)?
TH1 and TH 17
Based on experimental evidence of T helper responses (Warfel et al. 2013, Fig. 5), why does the wP vaccine seem to provide a better response against B. pertussis than the aP vaccine?
aP vaccination induces a TH2 response, while wP vaccination and natural infection induced a TH1 response, and a partial TH17 response. The response by TH17 and TH1 cells allows for the development of memory by the cells and protective immunity against future infections. This is compared to the aP vaccine that simply treats the symptoms and does not induce imunnologic memory, prevent colonization or transmission.
aP vaccine may protect abainst symptoms, but it can still spread from person to person, but with the wP vaccine however it can not
What was the importance in Warfel et al. 2013, Fig. 5 (right-side graphs) of showing that CD95-negative/CD4-positive (CD95- CD4+) cells did not produce cytokines (i.e. cytokines were only produced by CD95+ cells)?
When stimulated with heat-killed B. pertussis, both total nonadherent cells and CD4+ cells from convalescent animals secreted high levels of IL-17, some IFN-γ, and no IL-5.
When the CD95+ memory cells were depleted, the CD95–CD4+ cells did not secrete IL-17 or IFN-γ, consistent with induction of B. pertussis-specific Th17 and Th1 memory cells (Fig. 5). Stimulated total nonadherent cells and CD4+ cells from aP-vaccinated animals secreted significant IFN- γ, but the response was weaker than convalescent cells (P = 0.01), and there was no significant increase in IL-17 secretion. However, there was a significant IL-5 response, consistent with skewing toward Th2 and Th1 memory (Fig. 5).
Based on experimental evidence of T helper responses (Warfel et al. 2013, Fig. 5; asterisks denote statistically significant differences between negative control and experimental group), what is the polarized response produced by the acellular pertussis (aP) vaccine?
TH1 and TH2
Warfel et al. 2013 showed that the wP and aP vaccines induce different T cell responses with the wP vaccine being more similar to infection/recovery (convalescent animals). How can the aP vaccine be modified to produce a response similar to wP but without the adverse reactions?
If they were able to tailor the aP vaccine to stimulate a T-17 response, similar to that of the wP vaccine, they may see comparable effects. Using the aP vaccine that has the ability to stimulate that response, would decrease the likelihood that a person would have an adverse reaction due to the whole cell not being presented.
Which intracellular signalling complex is associated with the B cell receptor (BCR) and serves a similar function to the CD3 complex for TCR?
Ig-alpha and Ig-beta
