Lecture 11 Flashcards
What type of T lymphocytes recirculate through LN’s? What transports Ags into the LN’s and interacts with T cells until the specific Ag activates one?
Naive T lymphocytes recirculate through LNs
DCs transports Ags into LNs and transiently interact with T cells until one of them reacts
When T cells are activated, the differentiate into effector T cells. State the 2 locations that an effector T cell functions and what it’s functions will be based on the location it is in.
Some effector T cells may remain in the lymphoid organs and help B cells
Some effector T cells may migrate to the site of the infection and help activation macrophages
Ag recognition by T cells induces the secretion of what substance in order to stimulate proliferation/differentiation of the T cells into effector or memory cells? what is the term that describes this process?
IL-2 is secreted by T cells upon Ag recognition
Clonal Expansion: the proliferation/differentiation of T cells into Effector or memory cells
Compare the functions of CD4+ effector cells and CD8+ effector cells.
CD4+ effector cells: respond to Ags by producing cytokines which activate/recruit leukocytes and B cells
CD8+ effector cells: kill “infected/altered” host cells
True or False:
Effector CD8+ and CD4+ T cells both work to activate macrophages. explain.
True
Even though effector CD4+ cells don’t do any kind of cell killing themselves, and are mostly secreting cytokines, they still activate macrophages just like CD8+ T cells do.
State the 2 main functions of APCs when it comes to the role they play in guiding T cell response
- they display Ags
2. they provide “costimulatory signals”
State the 3 things that Ag recognition accompanied by Co-stimulation induces in T cells
- the secretion of cytokines
- Proliferation (clonal expansion)
- Differentiation into effector and memory T cells
State the 3 important signals that cause the proliferation and differentiation into effector and memory T cells (list them in the order they occur in). Also Identify which of these signals ensures that the T cell immune response is “Ag-specific”.
- Ag recognition (signal 1)
This is the signal that ensures the T cell immune response is “specific” - Costimulation (signal 2)
(CD28 on T cell ; CD80/86 on DC) - Cytokines (signal 3)
(these tell the T cell what specific type of T cell it will become ex. Th1, Th2, Cytotoxic, etc)
For the following APC’s, state what type of T cell(s) can recognize Ag’s they present.
Resident tissue Macrophages:
DCs:
B cells:
Resident tissue Macrophages: Effector T cells
DCs: Naive T cells and Effector T cells
B cells: Effector T cells
If an activated DC cell produces the cytokine IL-12, what happens?
IL-12 stimulates that “differentiation” of naive T cells into effector T cells
What type of cells express low levels of costimulatory molecules and can therefore conduct Ag recognition with a T cell but cannot conduct the costimulatory (2nd signal) that is needed to activate a T cell. What type of T cell behavior does this cause?
Unactivated (immature) DC’s are the cells that express low levels of costimulatory molecules
Unactivated DC’s, conducting ONLY Ag recognition with a T cell, can induce an “anergic (tolerant)” T cell
Give alternative names for B7-1 and B7-2 costimulatory molecules. What type of cells express these? What receptor interacts with CD80/CD86? what cell is this receptor found on?
B7-1 = CD80
B7-2 = CD86
These are expressed by activated APCs
CD80/CD86 interacts with CD28 receptors on T cells
True or False:
The entire family of CD28 receptors function to stimulate T cell responses when activated. explain.
False.
While stimulated CD28 family receptors CAN stimulate T cell responses, they all serve to help T cell responses find a BALANCED level of response
This means that CD28 family proteins may serve as activating or as inhibitory receptors, depending on the current level of T cell response and the receptor that is involved
In terms of the APC and T cell interactions, which of these expresses Ligands and which expresses Receptors?
APCs express ligands
T cells express receptors
For the following T cell receptors (all of which are members of the B7/CD28 family of receptors), explain what their function is when they are stimulated by a ligand from an APC.
CD28:
CTLA-4:
ICOS (Inducible T-cell costimulator):
PD-1:
CD28: costimulates naive T cells to produce regulatory T cells
CTLA-4: Negative regulation of immune responses
ICOS (Inducible T-cell costimulator): Causes costimulation of effector/regulatory T cells in order to generate follicular helper T cells
PD-1: causes negative regulation of T cells
Explain the method that CTLA-4 uses to regulate T cell responses and why it does this.
CTLA-4 negatively regulates T cell stimulation in a “dampening” method”.
This means that it forms a ceiling on the level of T cell stimulation, instead of just reducing the level of stimulation.
It does this in order to prevent apoptosis of the T cell, bc “overworked” T cells (that have levels of stimulation that are too high) will be stressed to the point that their stress signals cause them to conduct apoptosis.
When is the CTLA4-mediated immune checkpoint induced in naive T cells?
At the time of their initial response to an Ag
Describe the method by which CTLA-4 receptors are expressed by a T cell and compare it to the method by which CD28 is expressed.
Naive and memory T cells express high levels of surface CD28 receptors but DO NOT express CTLA4 until they are triggered by an Ag encounter
CTLA4 is stored in intracellular vesicles until Ag recognition via the TCR (and CD28) stimulates the CTLA4 to be transported to the surface of the cell
True or False:
The stronger the Ag stimulation through the TCR, the greater amount of CTLA4 will be expressed on the surface of the T cell. explain.
True
not much to explain
State the major role of the PD1 pathway AND the location in the body that this role is carried out.
(The major role of PD1 is NOT at the initial T cell activation stage)
The major role is to regulate the inflammatory responses in “Peripheral Tissues” by effector T cells
This limits collateral tissue damage to the tissues near the infection site
What type of signals in tissues induce the expression of PD1 ligands?
inflammatory signals
What is the best characterized signal for PDL1 induction? where is this signal derived from?
IFNgamma is the best characterized signal for the induction of PDL1 and it is derived from Th1 cells
If PD1 is excessively induced on T cells, such as what may occur in the setting of chronic antigen exposure, what occurs?
An Anergic state of the T cells
Activated T cells _____ PD1 and continue to express it in _____.
upregulate
tissues.
True or False:
PD-1 functions as a rheostat for immune responses and works at the molecular level. explain.
True
PD-1 can reduce the level of T cell activation by acting as a phosphatase to remove phosphates from adapter proteins in the T cell activation pathway (the one that uses AP1, NFAT, and NFKB)
Which of the 3 T cell activation “signals” determines the outcome of Ag recognition with regard to Effector T cell Differentiation?
Signal 3 (cytokines)
For the following cytokine, state the 3 transcriptional factors it stimulates (in order) and then state what specific type of T cell it will become:
IL-12
IL-12:
Activates STAT4
leads to the expression of T-bet
which facilitates the generation of Th1 cells
For the following cytokine, state the 3 transcriptional factors it stimulates (in order) and then state what specific type of T cell it will become:
IL-4
IL-4:
Activates STAT6
leads to the expression of GATA3
which facilitates the generation of Th2 cells
For the following cytokine, state the 3 transcriptional factors it stimulates (in order) and then state what specific type of T cell it will become:
IL-6
IL-6:
Activates STAT3
leads to the expression of RORgammat
which facilitates the generation of Th17 cells
For the following cytokine, state the 3 transcriptional factors it stimulates (in order) and then state what specific type of T cell it will become:
TGFbeta
TGFbeta:
Activates SMAD2-SMAD4
leads to the expression of FOXP3
which facilitates the generation of T regulatory cells
True or False:
T cells that express the same antigen receptor (signal 1) will also go on to respond to the same cytokine (signal 3). explain
False
Just bc T cells express the same antigen receptor (signal 1) and therefore respond to the same antigen, DOES NOT mean that they will also respond to the same cytokine
This creates a system that will create T cells that respond to the same antigen but will differentiate into different subtypes of T cells in order to fulfill all of the roles of the T cell immune response to the SAME ANTIGEN.
True or False:
Superantigen-induced polyclonal activation of T cells is not antigen specific. explain.
True
This is bc the superantigens only bind to the Beta subunit of the TCR portion of the TCR/MHCII complex
Ags binding to TCR’s ARE antigen specific because they bind in the peptide-binding groove that lies between the TCR and MHCII molecules (superantigens bind outside of this groove “on the side”)
Define superantigens and then describe what they stimulate T cells to do when they activate them. (3 specific substances to mention here)
Superantigens: the most powerful T cell Mitogens ever discovered
Superantigens induce a robust proliferation of T cells that produce massive amounts of Proinflammatory cytokines (TNF, IL-1, and IL-2) which may lead to shock
True or False:
Superantigens are more effective at stimulating T cells when they are processed by APC’s. explain
False
Superantigens are NOT PROCESSED into peptides
Describe the mechanism by which superantigens activate T cells and what determines whether or not a superantigen will be able to stimulate a T cell.
Superantigens prolongedly “glue” the TCR and MHCII molecules together in order to robustly activate T cells
SAgs bind ONLY to some beta units of the TCR and cannot bind to all Beta units (it has to be the correct/specific beta unit and each person’s genes are different)
Put the following proteins in order in terms of the order they are expressed after CD4+ T cell activation
CD69
IL2Ralpha
IL-2
CD40L
IL-2
CD69
IL2Ralpha
CD40L
(cell division then occurs)
IL-2 is an _____ growth factor for CD4+ and CD8+ T cells. State the property that IL-2 potentiates in NK cells and CD8+ cells.
Autocrine
Cytotoxicity
State the 3 cytokines that IL-2 stimulates T cells to produce
IL-4
IL-5
IFNgamma
IL-2 stimulates the survival, proliferation, and differentiation of Ag-activated T cells. State the 2 specific proteins that IL-2 interacts with in order to achieve this.
IL-2 induces the anti-apoptotic protein Bcl-2
IL-2 stimulates cell cycle progression by degradation of the cell cycle inhibitor p27
IL-2 is REQUIRED for the survival and function of what type of cells?
T regulatory cells
knockout mice for the IL-2 gene show selective defects in T regulatory cells
What is the major physiological function of IL-2?
To limit, rather than enhance, T cell responses
IL-2 does this by enhancing the presence of regulatory T cells which promote “peripheral self tolerance”
List, in the order that they are expressed, the surface cells of a T cell as it is activated and then the immune response of the T cell is controlled
- TCR
- CD69
- IL-2Ralpha (CD25)
- CD40L
- CTLA-4
Describe the function of CD69 and describe instances that may affect the level of activity of CD69
CD69 associates with, and inhibits the surface expression of S1PR1 receptors on T cells in lymph nodes
(S1PR1 receptors are surface molecules that must be present for lymphocytes to leave (egress) from the lymph nodes)
CD69 inhibits S1PR1 for 2 hours if no T cell activation occurs but it can change it’s activity level to up to 5 days long if the T cell is activated by an Ag in a LN
Describe what occurs to the level of CD69 expression after cell division occurs
CD69 expression decreases
Explain the mechanism by which S1PR1 receptors can guide a lymphocyte out of a LN once they are allowed to be re-expressed by CD69.
Lymphocytes use their S1PR1 receptors to detect and follow a high concentration of S1P in the lymph (out of the node)
This entire process is a chemotactic mechanism
What are the only type of cells that express CD25 (IL-Ralpha)? What does the expression of CD25 allow these cells to do?
Ag-activated T cells are the only cells that express CD25
An increased expression of CD25 allows Activated T cells to respond to IL-2’s proliferative signals
When an activated T cell is expressing CD25 in order to be able to respond to IL-2 signaling, explain the significance of the CD25’s IL-2Ralpha chain as opposed to the beta and gamma chains that also compose the CD25 receptor.
The expression of the alpha chain, which is added to the complex of other chains in order too form the full CD25 receptor (IL-2Ralphabetagammac), greatly increases the T cell’s affinity for IL-2
What induces the expression of CD40L on T cells? When is the expression of CD40L on T cells at it’s highest?
Ag recognition induces the expression of CD40L
CD40L expression is at it’s highest within 24-48 hrs after Ag recognition
Describe what the expression of CD40L has to do with APC’s and their B-7 molecules (CD80)
expression of CD40L enables APC’s to be “better” at their job
CD40L engages with CD40 on APCs and may stimulate the expression of B7 molecules and the secretion of cytokines that activate T cells
What controls the clonal expression of T cells? what regulates the contraction of this T cell immune response?
IL-2
The “starvation” of IL-2, caused by the elimination of Ags, which leads to the intrinsic pathway of apoptosis
Explain the relationship between the level of costimulation of T cells and the level of anti-apoptotic proteins in T cells
They are directly related
drop together and rise together
State the 3 regulatory mechanisms that contribute to the normal contraction of immune responses
- The inhibitory receptors CTLA4 and PD-1
- Apoptosis induced by death receptors TNFRI and Fas
- Inhibition by Treg cell products
There are 2 different proposed models that explain how memory T cells are developed, the Linear model and the BLimd differentiation model. Compare these and identify which of them is most consistent with recent findings on the topic.
Linear Model: describes that most effector cells die, however some persist and develop in to memory T cells
(THIS model is what is consistent with recent findings)
Branched Model: describes effector T cells and memory T cells are alternative fates of activated T cells
What type of cell is the most abundant lymphocyte population in the body during a person’s lifetime? where can you find the vast majority of these cells?
Memory T cells
The vast majority of these reside in tissue sites (lymphoid tissues, intestines, lungs, skin)
T-bet and Blimp-1 are 2 types of ____ ______ that are induced during T cell activation may influence the fate between the development of effector and memory T cells. Describe what each of these promotes.
Transcription factors
T-bet: drives the differentiation of effector cells in CD4+ T cells
Blimp-1: promotes the generation of memory cells
For the following subsets of memory T cells (for both CD4+ and CD8+) describe their function and the location they can be found.
Trm cells:
Tcm cells:
Tem cells:
Trm cells: Resident memory T cells
Are specific for pathogens that have been previously encountered
They remain in the tissue of primary response (they don’t leave)
Tcm cells: Central Memory T cells
Express chemokine receptor CCR7 and L-selectin and home to secondary lymphoid organs (spleen, LNs, and blood)
These Circulate through secondary lymphoid tissues
Tem cells: Effector Memory T cells
(DO NOT proliferate)
They either produce IFN-Gamma and TNF OR become cytotoxic
Circulate in the blood
For Tcm Cells, explain what they do upon re-exposure to the same antigen
Upon re-exposure, these proliferate (due to IL-2) and generate many effector cells
For Tem cells, explain what they do when they enter a tissue
Tem cells, upon entering a tissue, become Trm cells and reside in the epithelial barrier of the tissue (at the interface of the host and the environment)
For the 3 subdivisions of memory T cells below, describe which of the following they secrete, using + marks. IL-2, IFNgamma, and TNF
Trm cell:
Tcm cell:
Tem cell:
Trm cell: produce cytokines to help fight pathogens (no IL-2)
IL-2: - (none)
IFNgamma: +++
TNF: +++
Tcm cell: when reactivated, these produce clonal expansion (IL-2)
IL-2: +++
IFNgamma: ++
TNF: ++
Tem cell: produce cytokines to help fight pathogens (some IL-2)
IL-2: ++
IFNgamma: +++
TNF: +++
IFNgamma = potentiating property for macrophages TNF = inflammation
The maintenance of memory cells is dependent on cytokines and does not require Ag presence. What 2 cytokines are responsible for the low-level proliferation that keeps memory cells alive for so long?
IL-7 and IL-15 cytokines induce the expression of “anti-apoptotic” proteins in order to achieve the low-level of proliferation that allows memory cells to persist for so long
Compare between naive T cells and Memory T cells, the number of days it takes and the number of cells that are specific for the antigen
Memory T cells respond to the Ag in 1-3 days while naive T cells respond in 5-7 days
The number of lymphocytes specific for a pathogen is much greater in memory T cell response, compared to a naive T cell response
State the 3 phases that memory cells undergo throughout a person’s life and be sure to include the age range that these occur in.
Generation: occurs from age 0-20 and generates memory T cells from Ag exposure
Homeostasis: occurs from age 30-65 and memory T cell levels plateau
Immunosenescence: occurs from age 65-death and shows loss of CD28 expression that causes Tem cells (mainly from the CD8+ population) to accumulate
State the 4 things that are characterized by cells affected by immunosenecence
- decreased proliferative capacity
- Shortened telomeres
- Reduced TCR repertoire
- Enhanced cytotoxic activity
