Glossary Patho exam 2
FIRST SLIDE DECK: T Cell Immunology
Slide 35: Cytokines + T Cells and Cytokines
Big idea
The professor starts by saying we are at the point where T cells have been activated, and now we need to understand the output of that activation.
One major output, especially from helper T cells, is:
Cytokines = proteins that act as immune-system messengers.
They help immune cells communicate with each other and control:
Activation
Proliferation
Differentiation
Inflammation
Effector function
Cytokines are common throughout the immune system. Think about them in:
Inflammation
Innate immunity
Macrophage responses
B cell class switching
T cell activation
“The issue is they’re pleiotropic, they’re redundant, multiple cells will secrete the same cytokines.”
CD4 cells secrete much more cytokines than CD8 T cells
Important cytokine properties
1. Cytokines are transient
Transient = produced for a short time, then they go away.
For T cells, cytokines are produced in response to:
Antigen recognition
Co-stimulation
For activation of T- cells we’re looking
-signaling and co-stimulation for T- cells that will induce cytokines genes being transcribed depending on the signals and what the co-stimulatory cells are.
T cells do not just randomly make cytokines. They need to see antigen and receive proper activation signals.
2. Cytokines can act in different ways
Autocrine signaling = cytokine acts on the same cell that secreted it.
Example: activated T cell makes IL-2 and responds to IL-2 itself.
Paracrine signaling = cytokine acts on nearby cells.
Example: helper T cell secretes IFN-γ to activate a nearby macrophage.
3. Cytokines are pleiotropic
Pleiotropic = one cytokine can have many effects.
Example: IL-2 helps with T cell survival, proliferation, and differentiation.
4. Cytokines are redundant
Redundant = different cytokines can produce overlapping effects.
Example: TNF-alpha and IL-1, which both participate in inflammation and have similar effects.
Slide 35 continued: IL-2
IL-2 = T cell growth factor
“One of the key cytokines during the activation process for these activated T cells is IL-2. This is also known as T cell growth factor.”
Definition
IL-2 = cytokine made mainly by activated CD4 T cells that promotes T cell survival and proliferation.
IL-2 is secreted within 1–2 hours after activation by CD4+ T cells and induces survival and proliferation.
Who makes IL-2?
CD4 cells produce cytokines to a much greater degree than CD8 cells.
What IL-2 does
IL-2 causes:
T cell survival
T cell proliferation
Clonal expansion
Differentiation into effector cells
Support of regulatory T cell survival
*IL-2 is a growth factor, so it helps activated T cells expand clonally.
Slide 36: IL-2 Receptor and Cytokine Table
IL-2 receptor changes after activation
The slide diagram shows that naïve T cells initially express a low-affinity IL-2 receptor. After activation, they express a high-affinity IL-2 receptor.
IL-2 receptor has 3 chains molecules
Naïve T cells express only:
β chain
γ chain
This makes a low-affinity receptor.
After activation, T cells express:
α chain
β chain
γ chain
This makes a high-affinity IL-2 receptor.
Why does this matter?
The activated T cell is doing two things at once:
Secreting IL-2
Increasing high-affinity IL-2 receptor expression
So the T cell can respond strongly to its own IL-2 and proliferate.
The KD changes from about 10⁻⁹ to 10⁻¹¹, meaning the receptor binds IL-2 much more tightly.
CD8 can also do this to a lesser degree. They often rely on CD4 cells
Cytokine table: high-yield cytokines
IL-2
Main action:
Survival
T cell proliferation
Regulatory T cell survival
Source:
CD4+ and CD8+ T cells. (much more for CD4+)
IL-4
Main action:
B cell switching to IgE
Source:
CD4+ T cells
Mast cells
IL-5
Main action:
Activation of eosinophils
Source:
CD4+ T cells
Mast cells
Innate lymphoid cells
IFN-γ
Main action:
Activation of macrophages
Source:
CD4+ T cells
CD8+ T cells
NK cells
IL-17
Main action:
Stimulation of acute inflammation
Source:
CD4+ T cells
Other cells
TGF-β
Main action:
Inhibits T cell activation
Helps differentiation of regulatory T cells
Source:
CD4+ T cells
Many other cell types
Slide 37: Application — IL-2 Therapeutics
IL-2 is a target for drugs
Therapeutic agents that target IL-2
1. Monoclonal antibodies that antagonize IL-2 receptor
What would this do immunologically?
It would decrease T cell activation/proliferation.
Why?
If IL-2 cannot bind its receptor, T cells cannot expand well.
*If IL-2 is inhibited, T cells do not multiply as much after activation, which decreases the overall immune response by reducing both CD8 cytotoxic T-cell activity and CD4 helper T-cell expansion.
For example, drugs that target IL-2 are used to prevent transplant rejection
2. Infusions of IL-2
What would this do immunologically?
It would increase T cell proliferation/activation.
Why?
IL-2 is T cell growth factor -> stronger immune response.
3. Diphtheria toxin fused to IL-2
This fusion protein binds the IL-2 receptor α chain.
What would this do immunologically?
It targets activated T cells expressing the high-affinity IL-2 receptor and can kill them because the diphtheria toxin is delivered to those cells.
Big idea
Activated T cells express more IL-2 receptor α chain, so they become targets.
Slide 37 continued: T Cells — Clonal Expansion
Definition
Clonal expansion = rapid increase in antigen-specific T cell clones after activation.
The slide says that within 1–2 days of activation, there is a huge expansion of antigen-specific clones.
Why clonal expansion matters
Microbes divide quickly, so the immune system needs a large pool of antigen-specific T cells.
“Keep up with the microbial division.”
Important features of clonal expansion
1. It is antigen-specific
Only the T cells that recognized antigen expand.
“There’s no bystander increase.”
Even though IL-2 is around, not every T cell expands.
Only activated T cells with the proper receptor and IL-2 receptor respond strongly.
2. Most clones are specific for only a few antigens
The immune response expands the most useful clones.
3. CD8 expansion is greater than CD4 expansion
Expansion of CD8+ cells is 100–1000 fold greater than CD4+ expansion.
Why?
CD8 cytotoxic T cells need to physically contact infected target cells to kill them, so the body needs more of them.
CD4 helper T cells secrete cytokines, which can affect nearby cells, so fewer CD4 cells may be needed.
Slide 38: T Cell Differentiation — Effector Cells
Definition
Effector T cell = activated, differentiated T cell that can perform immune functions.
Differentiation occurs late in proliferation, after about 3–4 days of rapid growth.
What changes during differentiation?
Differentiation occurs through changes in gene expression.
Effector cells begin making molecules needed for their specific jobs.
If helper T cell:
It makes cytokines and surface molecules to help other cells.
If cytotoxic T cell:
It makes killing proteins.
Major features of effector T cells
1. They no longer need full co-stimulation
Naïve T cells require lots of signals:
Antigen
MHC
Co-stimulation
Cytokines
Effector T cells are easier to activate, encountering specific antigen is enough.
However they still need to see their antigen on MHC in the periphery.
2. They change adhesion molecules and receptors
This allows them to move to infection sites.
Slide 38 Clicker Question:
“Which of the following is considered or are considered effector cells?
Cytotoxic T cell = activated CD8 effector cell
Helper T cell = activated CD4 effector cell
*a cytotoxic T-cell, meaning it’s CD8 positive and it’s been activated and it’s in its effector form.
Slide 38 continued: Types of Effector T Cells
Naïve CD8 T cells
Differentiate into: CD8 cytotoxic T cells
Also called: CTLs = cytotoxic T lymphocytes
Function: Kill target cells
Naïve CD4 T cells
Differentiate into multiple helper subsets:
TH1
TH2
TH17
Regulatory T cells
Slide 39: CD4+ Helper T Cells — Activation
Main function
CD4 helper T cells activate other immune cells.
CD4+ helper T cells respond to antigen by producing surface molecules and cytokines that activate:
Phagocytes
B cells
“They’re helping. That’s their job.”
CD40L = CD40 ligand, a surface molecule expressed on activated helper T cells.
CD40L gene transcription occurs in response to antigen recognition and co-stimulation.
CD40L binds: CD40 on the macrophage
CD40 is found on:
Macrophages
B cells
Dendritic cells
Helper T cell + macrophage interaction
A helper T cell recognizes antigen on a macrophage MHC class II.
Because CD4 T cells recognize: MHC class II
Then the helper T cell provides help through:
CD40L binding CD40
Cytokine secretion
Activation of CD4 cells
Result: The macrophage kills microbes better.
Helper T cell + B cell interaction
The same idea applies to B cells.
B cells present peptide on: MHC class II
Helper T cells bind and provide:
CD40L
Cytokines
Result:
B cells can undergo:
Plasma cell differentiation
Antibody secretion
Isotype switching
Better antibody responses
*different cytokines from helper T cells drive different antibody classes.
Slide 40: Development of Memory T Cells
Definition
Memory T cells = long-lived T cells formed after antigen activation that respond faster upon re-exposure.
Some antigen-activated T cells become long-lived memory cells and survive after infection is cleared.
They are found in:
Lymphoid organs
Mucosal tissues
Circulation
They respond rapidly when they see antigen again.
Types of memory T cells
1. Central memory T cells
Respond more slowly.
2. Effector memory T cells
Respond more quickly.
What keeps memory T cells alive?
Memory T cells need:
IL-7
IL-15 for memory maintenance.
-Factors that determine whether the antigen-stimulated progeny of an activated T-cell becomes memory cells or differentiates into effector cells right away? Not clear
Slide 40 continued: CD8 Effector T Cells — Development
Naïve CD8 T cells become CTLs
The slide says naïve CD8+ T lymphocytes are activated by:
MHC I + antigen
Co-stimulation
Then they differentiate into:
Cytotoxic T lymphocytes, CTLs
CTLs kill infected cells expressing the antigen that they regonize.
What do CTLs use to kill?
CTLs synthesize killing proteins that:
Create pores in infected cell membranes
Induce DNA fragmentation
Induce apoptosis
“Similar because it’s what the NK cells do.”
Slide 42: Naïve T Cell Entry Into Lymph Nodes
Big idea
Naïve T cells constantly circulate and need to enter lymph nodes to look for antigen.
They enter lymph nodes using:
Chemokines
Chemokine receptors
Adhesion molecules
Adhesion molecules on naïve T cells
The slide lists:
L-selectin
LFA-1
CCR7
L-selectin
Helps naïve T cells enter lymph nodes.
LFA-1
An integrin that helps cells bind tightly.
CCR7****
Chemokine receptor that guides naïve T cells into T cell zones.
Molecules on high endothelial venules, HEVs
HEVs express:
L-selectin ligand
ICAM-1
ICAM-1 binds LFA-1.
Key concept
Chemokines direct T cells to lymph nodes and activate integrins for stronger binding.
Slide 42 continued: Effector T Cells Can Get to Infection Sites
Effector T cell migration depends on:
2 Adhesion molecules on T cells
Chemokine receptors on T cells
Ligands on endothelium at the infection site
Chemokines made at the infection site
Differentiation into effector cells is accompanied by changes in adhesion molecules and chemokine receptors.
Slide 43: Effector T Cell Entry Into Tissues
Activated T cells express different molecules
The effector T Cells express different molecules
They’re not the same as naive cells but they are derived from them and so they express different adhesion molecules in their activated form so different ligands for selections are found.
On endothelium and different integrins allows them to match the molecule on the endothelium at the site of infection.
These interactions allow effector T cells to leave blood and enter infected tissues.
Chemokines at infection sites
Chemokines are often produced by innate immune cells.
They:
Attract effector T cells
Activate integrins
Improve binding
Help cells enter tissues
Think about innate immune cell migration, where cells roll, then stick tightly, then move through endothelium.
Slide 43 continued: S1P and T Cell Migration
S1P = sphingosine 1-phosphate***
Definition
S1P = lipid signaling molecule found at higher concentration in blood and lymph than inside lymph nodes.
T cells follow the S1P gradient to exit lymph nodes.
How S1P controls T cell movement
Naïve T cells in circulation
Naïve T cells express some S1P receptors. At low expression.
They can respond to S1P and circulate through blood/lymph.
If naïve T cell enters lymph node and does NOT find antigen
It keeps enough S1P receptor to leave the lymph node and back into the blood to continue circulating.
If naïve T cell finds antigen on MHC
It downregulates the S1P receptor.
This keeps it inside the lymph node so it can stay with the dendritic cell and become activated.
This helps explain why T cells can remain attached to dendritic cells for days. HAS LESS OF THE RECEPTOR NOW
After activation/differentiation
The effector T cell increases S1P receptor expression again.
Then it follows the S1P gradient out of the lymph node into blood/lymph following a chemokine trail.
*S1P helps T cells leave lymph nodes. If a T cell recognizes antigen, it decreases S1P receptor expression so it stays in the lymph node for activation; after activation, it increases the receptor again and exits to circulate in the blood and fight the infection
Slide 44: Homing Is Independent of Antigen Recognition
Big idea
Where a T cell goes is based on its adhesion molecules and chemokine receptors, not the antigen it recognizes.
“Homing: independent of what Ag is recognized.”
For T cells, homing is like having an address/GPS system that tells them where to go
Important exam point
Effector T cells enter inflamed tissue non-selectively.
That means any effector T cell can enter an infection site if it has the right migration molecules.
But only T cells that recognize antigen at that site will stay and function.
Example from professor
If you have two infections:
Staph aureus on skin
E. coli in urinary tract
Effector T cells for both may enter inflamed areas because inflammation/chemokines attract them.
But:
E. coli-specific T cells will not stay at the Staph site
They will move on until they find E. coli antigen
Slide 45: Decline of Immune Response
Big idea
After infection is cleared, the immune response must return to normal.
This is called: Homeostasis
The response returns to steady state when survival and maintenance signals are removed.
Signals removed include:
Antigen
Co-stimulation, like CD28 signals
Cytokines, like IL-2
What happens to effector T cells?
Most die by: Apoptosis
The response usually subsides within:
1–2 weeks after infection is eradicated
What remains? Memory T cells
SECOND SLIDE DECK: Effector Mechanisms of Cell-Mediated Immunity
Slide 2: Background / Refreshers
Big idea
T cells mediate:
Cell-mediated immunity
This is part of adaptive immunity.
T cells are especially important for: getting rid of Intracellular microbes
T cells are essential for combatting intracellular microbes and help combat extracellular microbes too.
Two major effector T cell types
CD4 helper T cells
They secrete cytokines that recruit and activate other leukocytes.
Example:
They help phagocytes destroy microbes.
Help B cells differentiate and form plasma cells and isotype switch and have affinity maturation
CD4 helper T cells recognize antigens presented on:
MHC class II
These antigens often come from vesicles.
CD8 cytotoxic T cells, CTLs
They kill cells with microbes or microbial proteins in the cytosol.
CD8 cytotoxic T cells recognize antigens presented on:
MHC class I
These antigens often come from the cytosol.
Where are effector T cells generated?
Effector T cells are generated from naïve T cells stimulated in:
Lymph nodes
Spleen
(MALT or GALT)
Then they migrate to infection sites.
Slide 3: Naïve T Cells on the Prowl
Main idea
Naïve T cells circulate through:
Blood
Lymph
Lymphoid tissues
They meet dendritic cells in lymphoid tissues.
The professor repeats the phrase:
“Sample the wares.”
Meaning:
T cells scan peptide:MHC complexes on dendritic cells.
If a naïve T cell finds its specific antigen:MHC complex on a mature dendritic cell:
Migration stops
Proliferation begins
Clonal expansion occurs
Differentiation proceeds
Slide 4: Microbes Meet T Cells
Infections can occur anywhere
Some microbes live inside host cells.
Examples:
Bacteria and protozoa can live in phagocytes.
They may resist killing and survive in:
Vesicles
Cytoplasm
Viruses
Infect and live in the cytoplasm of:
Non-phagocytes
Phagocytes
Effector T cells migrate to infection sites
Effector T cells are generated in lymphoid tissues, then migrate to sites of infection.
At infection sites, they recognize antigen:MHC on infected cells and respond. Need less co-stimulation there but one key thing is CD40 ligand on the T-cell and CD40 on whatever they’re interacting with.
CD40L on T cells binding CD40 on target cells is key because it amplifies activation, especially by activating macrophages and helping B cells class switch
Slide 5: Helper Functionality
Helper T cell functions
Cell-mediated immunity
Allergic response
Inflammation
B cell antibody responses
Immunosuppression/regulation of autoimmunity
Major helper subsets from slide image
TH1
Defining cytokine ->IFN-γ
Target cell: Macrophages
Host defense: Intracellular pathogens
TH2
Defining cytokines:
IL-4
IL-5
IL-13
Target cells -> Eosinophils and mast cells
Host defense: Parasites (Helminths)
Disease association: Allergy
TH17
Defining cytokines:
IL-17
IL-22
Target cells -> Neutrophils
Host defense: Extracellular pathogens
Disease association: Autoimmunity/inflammation
Slide 6: Cytokine Summary
This slide repeats selected cytokines and their actions.
High-yield:
IL-2 → T cell proliferation and Treg survival
IFN-γ → macrophage activation
IL-4 → B cell switching to IgE
IL-5 → eosinophil activation
IL-17 → acute inflammation
IL-22 → epithelial barrier function
TGF-β → inhibition of T cell activation and Treg development
Slide 7: CD4 Effector T Cells — TH1 Cells
TH1 main job
TH1 cells activate macrophages.
The slide says TH1 cells:
Stimulate phagocytosis and killing of microbes
Activate macrophages through CD40L-CD40 interactions
Produce IFN-γ
IFN-γ = cytokine that activates macrophages and promotes cell-mediated immunity against intracellular microbes.
Functions:
Activates macrophages
Stimulates antibody isotypes that promote phagocytosis
Amplifies T cell responses
Increases MHC class II and B7 expression on macrophages and dendritic cells- -
This is helpful to get more naive cells activated.
Slide 8: TH1-Mediated Macrophage Activation
Step-by-step
1. Macrophage eats microbe
The microbe is inside the macrophage’s phagolysosome.
2. Macrophage processes microbe
It displays peptide antigen on:
MHC class II
3. TH1 cell recognizes antigen
The TH1 cell recognizes peptide:MHC II using its TCR.
4. TH1 expresses CD40L
CD40L binds CD40 on the macrophage.
5. TH1 secretes IFN-γ
IFN-γ activates the macrophage.
The slide says the macrophage must be in direct contact with the T cell because CD40 must bind CD40L.
What activated macrophages do better
Activated macrophages increase:
Lysosomal proteases
Reactive oxygen species, ROS
Nitric oxide, NO
IL-12
TNF
IL-1
Chemokines
ROS and NO - help kill microbes.
IL-12 - Promotes more TH1 differentiation.
Explains why it is considered positive feedback cycle:
“More IFN-gamma, more IL-12, more IFN-gamma, more IL-12.”
TNF, IL-1, chemokines - promote inflammation and recruit more immune cells.
Slide 9: TH1 Effector Cells — Macrophage Activation and DTH
TH1 activation is antigen-specific
Macrophage activation depends on antigen recognition.
Meaning:
The TH1 cell only activates macrophages presenting the antigen that the TH1 cell recognizes.
Delayed-type hypersensitivity, DTH = delayed inflammatory reaction mediated by TH1 cells and macrophages.
Same reaction as macrophage activation and is elicited by injecting microbial protein into the skin.
Why is it delayed?
It takes time because circulating effector T cells must:
Come to the injection site
Recognize antigen
Respond
Induce inflammation
Reaction appears around:
24–48 hours
TB skin test example
The TB skin test uses tuberculosis antigen, not the whole organism.
If a person has been exposed to TB or vaccinated with BCG, T cells respond at the injection site.
You see:
Inflammation
Edema
Fibrin deposition
Tissue damage
Hypersensitivity reactions are basically normal immune reactions happening in an unwanted context. Same as allergic response.
Slide 10: TH1 Subset Development
What drives TH1 differentiation?
TH1 development is driven by:
IL-12
IFN-γ
Sources:
Macrophages
Dendritic cells
NK cells
Innate immunity drives adaptive immunity
Meaning:
The innate immune response senses the microbe first and produces cytokines that tell naïve CD4 T cells what helper subset to become.
TH1 feedback loop
Intracellular microbe activates macrophages/dendritic cells/NK cells
These produce IL-12 and IFN-γ
Naïve CD4 T cell becomes TH1
TH1 produces IFN-γ
IFN-γ activates macrophages
Macrophages produce IL-12
More TH1 development
**Innate response → cytokines → TH1 differentiation → TH1 helps macrophages more
Slide 11: CD4 Effector T Cells — TH2 Cells
TH2 main job
TH2 cells are important for defense against:
Helminth parasites
TH2 cells stimulate phagocyte-independent, eosinophil-mediated immunity.
Key TH2 cytokines
IL-4
Functions:
Stimulates IgE production
IgE activates mast cells
IgE binds eosinophils
IL-5
Functions:
Activates eosinophils
IL-4, IL-10, IL-13
Function:
Limit injurious macrophage activation
Promote alternative macrophage activation
Healing is the response
Slide 11 continued: TH2 Effector Effects
Parasite response
TH2 cells produce IL-4
IL-4 causes B cells to switch to IgE
IgE binds mast cells and eosinophils
TH2 cells produce IL-5
IL-5 activates eosinophils
Mast cells and eosinophils release granule contents
Parasites are killed or expelled
What mediators are released?
Mast cells and eosinophils release preformed mediators such as:
Histamine
Proteases
Other inflammatory mediators
These can cause:
Smooth muscle contraction
Increased mucus
Sneezing
Increased peristalsis
Expulsion of parasites
Allergy connection
This same response is useful against parasites but causes allergies when misdirected.
Example:
Tree pollen
Grass pollen
The immune system is using a parasite-type response against harmless environmental antigens.
Alternative macrophage activation
Classically activated macrophages, M1
Driven by:
IFN-γ
Microbial products
Functions:
Microbial killing
ROS
NO
Lysosomal enzymes
Inflammation
Alternatively activated macrophages, M2
Driven by:
IL-4
IL-13
Functions:
Anti-inflammatory effects
Wound repair
Fibrosis
IL-13 acts on fibroblasts to increase collagen synthesis and fibrosis.
Slide 12: TH2 Diagram + Macrophage Activation Comparison
TH2 diagram summary
The slide shows helminths/protein antigens activating APCs and leading naïve CD4 T cells to become TH2 cells.
TH2 cells then produce:
IL-4
IL-5
IL-13
Effects:
IgE production
Anti-helminth antibodies
Mast cell degranulation
Intestinal mucus secretion and peristalsis
Eosinophil activation
Alternative macrophage activation.
(Lecture stopped here)
M1 vs M2 macrophages
M1 macrophages
Activated by:
Microbial products
IFN-γ
Produce:
ROS
NO
Lysosomal enzymes
IL-1
IL-12
Chemokines
Main outcome:
Microbicidal activity
Inflammation
M2 macrophages
Activated by:
IL-4
IL-13
Produce:
IL-10
TGF-β
Main outcome:
Anti-inflammatory effects
Wound repair
Fibrosis
Final High-Yield Exam Summary
Cytokines
IL-2 = T cell growth factor
IL-4 = IgE class switching
IL-5 = eosinophil activation
IFN-γ = macrophage activation
IL-17 = inflammation
TGF-β = Treg development/suppression
Effector T cells
CD8 effector = CTL = kills infected cells
CD4 effector = helper T cell = secretes cytokines
TH1 = macrophage activation
TH2 = helminths/allergy/eosinophils/IgE
TH17 = inflammation/neutrophils
Treg = suppression/tolerance
TH1
Driven by IL-12 and IFN-γ
Produces IFN-γ
Activates macrophages
Helps kill intracellular/vesicular microbes
Involved in DTH reactions
TH2
Driven by IL-4
Produces IL-4, IL-5, IL-13
Helps fight helminths
Causes IgE production
Activates eosinophils
Involved in allergies
Promotes M2 macrophage/wound repair pathway
T cell migration
Naïve T cells enter lymph nodes using CCR7
Effector T cells enter inflamed tissues using different adhesion molecules and chemokine receptors
Homing is antigen-independent
Staying/functioning is antigen-dependent
T cell response decline
When antigen, co-stimulation, and IL-2 decrease, effector T cells die by apoptosis
Memory cells remain