Handout 10: Differentiation and Functions of CD4+ T cells Flashcards
How many T cells have a specific TCR that can recognize a given pathogen? What do these T cells with specific TCRs that recognize pathogens do?
1 in 10^6 T cells
These T cells are mobilized and activated
Specific T cells are made by the immune system _____
On demand
Most of the T cells in ciruculation (90-95%) have what type of TCRs?
They have alpha beta TCRs
What do alpha beta TCRs recognize/bind to? What kind of co-receptors do they express?
They recognize/bind to both peptides presented within the MHC molecules and MHC itself
They express either CD4 or CD8 co-receptors
alpha Beta T cells are ______
MHC restricted
Ag recognition involves _______
clustering of TCRs
How is activation of T cells initiated?
By a signaling cascade after TCRs (at least two) recognize a specific Ag
Which parts of the alpha beta TCR signals and which parts are not long enough to signal?
The alpha and Beta chains have only a very short intracellular domain so signaling is mediated by other proteins comprising the TCR complex. CD3 proteins (gamma, delta, epsilon and zeta) have cytoplasmic tail that is long enough to signal
What components are required to activate a T cell?
TCR, CD4 or CD8, and CD3 to activate a T cell. CD4 is needed for T helper cells while CD8 is needed for cytotoxic T lymphocytes (CTLs)
What marker is used for counting total numbers of T cells (CD4 + CD8 T cells)
CD3
What is required to interview naive T cells? How many T cells can in interview per hour?
Activated DC required. Interviews about 500 naive T cells per hour
______ are immature dendritic cells that do not express high levels of B7
Langerhans’ cells
What is the process by which dendritic cells stimulate naive T cells?
- Ag uptake by Langerhan’s cells in the skin
- Langerhan’s cells leave the skin and enter the lymphatic system
- Langerhan’s cells enter the lymph node to become dendritic cells expressing B7
- B7-positive dendritic cells stimulate naive T cells
After the TCR is engaaged and activates T cell, what must the T cell receive?
Co-stimulatory signal
What are the co-stimulatory molecules expressed on professional APC?
B7 proteins (CD80/CD86)
B7 molecules plug into _____ expressed on T cells
CD28 receptor
What is the purpose of co-stimulation?
It’s an amplifier that improves the signal; with co-stimulation, we need about 100 fewer clustered TCRs for activation
What does CD80-CD26 Co-stimulation lead to?
Leads to proliferation and differentiation of T cells specific for a bacterial protein
What happens after T cell activation is completed?
The T helper cell and the APC are separated, and the APC goes on to activate other T cells. The T cells proliferate to increase their numbers.
What is required for the proliferation of T cells and is also called T cell growth factor?
IL-2
Do all T cells have IL-2 receptors (IL-2R) expressed on their surface? If not, which which T cells express IL-2R and which do not?
No, naive T cells do not have IL-2R expressed on their surface. Activated T cells, in contrast produce large amounts of IL-2 and express IL-2R.
Aside from T cell proliferation, what is another function of IL-2?
It enhances resistance of activated T cells to apoptosis
What are the steps in T cell proliferation?
- T cell is activated by Ag and costimulator
- IL-2 is secreted
- IL-2R alpha chain is expressed which results in formation of a high-affinity IL-2R alpha-beta-gamma complex (without the alpha chain, there is low affinity for the T cell)
- IL-2 induced T cell proliferation occurs
What are the phenotypic subsets of CD4 + T cells? These are all what kinds of cells?
Th1, Th2, & Th17 cells. These are all CD4 positive helper cells
Th1 cell Cytokine required to convert CD4+ into Th1 subtype: Signature cytokines: Immune reactions: Host defense: Role in diseases:
Cytokine required to convert CD4+ into Th1 subtype: IL-12
Signature cytokines: IFN gamma
Immune reactions: Macrophage activation; IgG production
Host defense: Intracellular microbes
Role in diseases: Autoimmune diseases; tissue damage associated with chronic infections
Th2 cell Cytokine required to convert CD4+ into Th2 subtype: Signature cytokines of Th2: Immune reactions: Host defense: Role in diseases:
Cytokine required to convert CD4+ into Th2 subtype: IL-4
Signature cytokines: IL-4, IL-5, IL-13
Immune reactions: Mast cell, eosinophil activation; IgE production; “alternative” macrophage activation
Host defense: Helminthic parasites
Role in diseases: Allergic diseases
Th 17 cell Cytokine required to convert CD4+ into Th17 subtype: Signature cytokines: Immune reactions: Host defense: Role in diseases:
Cytokine required to convert CD4+ into Th17 subtype: IL-23
Signature cytokines: IL-17A, IL-17F, IL22
Immune reactions: Neutrophilic, monocytic inflammation
Host defense: Extracellular bacteria, fungi
Role in diseases: Autoimmune inflammatory diseases
Activated T cells do no produce cytokines randomly. Each subset of T helper cells produces particular set of cytokines to carry out specific functions. What are the functions of each subset of T helper cells (Th1, Th2, Th17)? What is this process called?
Th1 cells are used to activate a cell-mediated immune response
Th2 cells activate an Ab-mediated immune response
Th17 cells are involved in inflammation and anti-bacterial response
Process is called differentiation or commitment of T helper cells
What is the sequence of events leading to T helper cell subtype differentiation?
Naive CD4 uncommitted cell–>proliferating T cell–>Immature T cell (Th0)–>Th1 cell or Th2 cell
What is the function of Th1 cell? What is the function of Th2 cell?
Th1 cell: Activates macrophages, induces B cells to produce opsonizing Ab
Th2 cell: Activates B cells to make neutralizing Ab; has various effects on macrophages
What forms an important bridge between innate and adaptive immunity?
Pathogen recognition by immature Dendritic Cells through Pattern Recognition Receptors (PRRs)
- Pattern Recognition Receptor (PRR) signaling causes activation and maturation of ______ which processes Ag and is presented to _____.
- _____ assists in the development and differentiation of Th1 cell
- Differentiation of _____ and ____ occurs in similar manner
- Antigen Presenting Cell, naive Th0 cells
- IL-12
- Th2 and Th17
What produces IL-12? What produces macrophages and IFN-gamma?What does IL-12 and IFN-gamma activate? This stimulates what?
DCs produce IL-12, NK cells produce macrophages and IFN gamma
IL-12 and IFN-gamma activate transcription factors T-bet, STAT1, and STAT4, which stimulates differentiation of naive CD4+ T cells into Th1 subset
What is the role of IFN-gamma in Th1 subset differentiation?
It amplifies the differentiation of CD4+ cells into Th1 subset and INHIBITS the development of Th2 and Th17 cells
What produces the cytokine IL-4? What transcription factors does IL-4 activate and why?
Activated T cells, mast cells and eosinophils produce IL-4
IL-4 activates GATA-3 and STAT-6 to stimulate the differentiation of naive CD4+ T cells to the Th2 subset
IL-4 produced by ____ amplifies the differentiation of CD4+ T cells to the ____ subset. What else does it do?
Th2, Th2
It also inhibits the development of Th1 and Th17 cells
What cytokines are involved in the development of Th17 cells? What transcription factors do these cytokines activate?
IL-1, IL-6 and IL-23 which activate transcription factors RORgamma-t and STAT3
Which cytokine is the most important cytokine in differentiation of Th17 cells?
IL-23
What transcription factor promotes Th17 responses by suppressing Th1 and Th2 cells? Why is this suppression necessary?
TGF-beta; suppression is necessary because Th1 and Th2 both inhibit Th17 differentiation
Which cytokine amplifies Th17 responses?
IL-21
T cell cytokine: IL-2
Principal action:
Cellular Sources:
Principal action: T cell growth stimulation
Cellular Sources: CD4+ and CD8+ T cells
T cell cytokine: IL-4
Principal action:
Cellular Sources:
Principal action: B cell switching to IgE
Cellular Sources: CD4+ T cells, mast cells
T cell cytokine: IL-5
Principal action:
Cellular Sources:
Principal action: Activation of eosinophils
Cellular Sources: CD4+ T cells, mast cells
T cell cytokine:IFN-gamma
Principal action:
Cellular Sources:
Principal action: Activation of macrophages
Cellular Sources: CD4+ and CD8 + T cells, natural killer cells
T cell cytokine: TGF-beta
Principal action:
Cellular Sources:
Principal action: Inhibition of T cell activation
Cellular Sources: CD4+ T cells; many other cell types
Cytokine: IL-17
Principal action:
Cellular Sources:
Principal action: Protection from extracellular pathogens; inflammation and autoimmunity
Cellular Sources: Th17 cells, gamma-delta T cells, Mf
What is the location where naive CD4+ Th0 cells recognize derived peptides and where these Ags are presented to the T cell by Dendritic Cells?
Lymph Nodes
After Ag is presented to T cells by DCs in LNs, where does the Ag activated effector CD4+ T cell go?
It enters the circulation and migrates to the site of Ag. Effector T cells migrate through blood vessels in peripheral tissues
Once effector T cells recognize the Ag in the tissue, how does it respond to the Ag?
It responds by secreting cytokines. Then, the cytokines recruit more leukocytes and activate phagocytes to eradicate the infection
Which subset of CD4+ T cells carry out cell-mediated immunity? Which subset carries out humoral immunity?
Th1 cells carry out cell mediated immunity and uses macrophages while Th2 cells carry out humoral immunity and uses Ag specific B lymphocytes
What are the effector functions of activated macrophages, B lymphocytes in Th1 vs. Th2 cells?
Th1 cells: Macrophage activation and killing of phagocytosed microbes
Th2 cells: Ab secretion; neutralization and elimination of Ag
What are the functions of Th1 cells?
Classical macrophage activation (enhanced microbial killing)
Complement binding and opsonizing IgG Abs
(uses IFN-gamma)
Macrophages are activated by Th1 cells. What are the specific responses of the activated macrophages?
Enhanced killing of phagocytosed bacteria
Secretion of inflammatory cytokines
Increaased expression of molecules required for T cell activation
One of the macrophage responses activated by Th1 cells is production of reactive oxygen species, nitric oxide, and increased lysosomal enzymes. What role does this specific function play in cell mediated immunity?
Killing of microbes in phagolysosomes (effector function of macrophages)
One of the macrophage responses activated by Th1 cells is secretion of cytokines and chemokines. What is the role of these cytokines/chemokines in cell mediated immunity?
TNF and IL-1 chemokins: leukocyte recruitment (inflammation)
IL-12: Th1 differentiation, IFN-gamma production
One of the macrophage responses activated by Th1 cells is increased expression of B7 costimulators, MHC molecules. How does this play a role in cell mediated immunity?
Increased T cell activation (amplification of T cell response)
What are the functions of Th2 cells? What cytokines are used for each function?
Ab production (IL-4)
Mast cell degranulation (IL-4)
Intestinal mucus secretion and peristalsis (IL-4, IL-13)
Eosinophil activation (IL-5)
Alternative macrophage activation (tissue repair) (IL-4, IL-13)
What is the difference between classically activated macrophage (M1) and Alternatively activated macrophage (M2)?
Classically activated has 2 functions:
- microbicidal actions: phagocytosis and killing of many bacteria and fungi via ROS, NO, lysosomal enzymes
- Inflammation via IL-1, IL-12, IL-23, chemokines
Alternatively activated, M2 has anti-inflammatory effects (wound repair, fibrosis) and uses IL-10, TGF-beta
What are the functions of Th17 cells?
Forms anti-microbial peptides
results in inflammation, neutrophil response (via TNF, IL-1, IL-6, CSFs)
Increased barrier function
What is the difference between IL-17 and IL-22 in terms of its relationship to Th17 differentiation?
IL-17 is used to differentiate Th17 cells into leukocytes and tissue cells while IL-22 is used to differentiate Th17 cells into tissue cells
What is the difference between how CD8+ T cells are activated vs. how CD4+ T cells are activated?
No difference. CD8+ T cells are activated in the LN by dendritic cells loaded with Ag just like CD4+ T cells
CTLs recognize ______
class I MHC associated peptides
After CD8+ cells are activated, what do they do?
They proliferate and leave the LN
CD8+ T cells are activated by mechanisms that involves ______
Cross-presentation of Ags to CD8+ T cells
Cells infected with intracellular microbes such as viruses are ingested by ____
Dendritic cells
Extracellular Ags are processed and presented within class II MHC, but they are also presented in associated with class I MHC. How?
Via Ag cross-presentation–some viral Ags are released from phagosome in cytoplasm of DC and then presented within class I MHC. The same cross-presenting APC then may display microbial peptides within class II MHC for CD4+ helper T cells
How do CD4+ T cells help in the activation of CTLs?
CD4+ helper T cells can produce cytokines that stimulate CTL differentiation OR
CD4+ helper T cells enhance the ability of APC to stimulate CTL differentiation
Does CTL differentiation always require the help of CD4+ helper T cell?
No, CTLs can also be differeniated using CD8+ T cells:
CD8+T cells recognize Ag + costimulators on professional APC which leads to CTL differentiation without helper T cell
CD8+ T cells are activated in the LN by DCs loaded with Ags exactly as _____. CTLs recognize _____ on infected cells. Activated CD8+ cells proliferate and leave the ____
CD4+ T cells, class I MHC-associated Ag, LN
After CTL is activated, what are the granules that CTLs release/exocytose? What is the purpose of these granules?
perforin and granzyme; they induce apoptosis in the target cell
CD8+ T lymphocytes also secrete ____ which activates macrophages.
IFN-gamma
What are non-traditional T cells? Why are they non-traditional?
They have gamma-delta TCRs and CD3. They do NOT express CD4 or CD8 co-receptors
Where are non-traditional T cells (gamma-delta T cells) found? Are they “educated” in the thymus?
Intestine, uterus, and tongue
Not known whether they are educated in thymus
What are the functions of gamma-delta T cells?
They are the first line of defense
Regulatory cell
Bridging between innate and adaptive responses
What characteristics qualify gamma-delta T cells as being a component of adaptive immunity?
Rearrangement of TCR genes to produce junctional diversity
Development of a memory phenotype
What characteristics qualify gamma-delta T cells as being a component of innate immunity?
A restricted TCR may be used as a pattern recognition receptor
Which is more diverse–gamma-delta TCRs or alpha-beta TCRs?
alpha-beta TCRs are more diverse
that gamma-delta TCRs recognize what kinds of Ags?
UNPRESENTED Ags
The function of gamma-delta T cells is still not clearly understood, but what is one possible function of these cells?
They kill cells that become stressed as a result of microbial infection
What are Natural killer T (NKT) cells?
A heterogenous group of T cells that share properties and CD markers of both T cells and NK cells
What do NKT cells recognize? How much of the peripheral blood T cells do they make up?
self- and foreign lipids and glycolipids
Only makes up 0.2% of all peripheral blood T cells
Lipid and glygolipids should be presented within what kind of molecule?
non-polymorphic CD1d molecule-Ag presenting complex like MHC
What cytokines do NKT cells produce in large amounts? What is the purpose of releasing these cytokines?
IFN-gamma, IL-4, and GM-CSF (granulocyte-macrophage colony-stimulating factor)
NKT cells rapidly release these cytokines to promote or suppress different immune responses
What are some of the consequences of deficiency/dysfunction of NKT cells?
Autoimmunity (diabetes or artherosclerosis)
Cancers
Progression of asthma
