Immuno 7: T Cell Activation/Differentiation Flashcards
Naive T cells can only be activated by what?
a professional antigen presenting cell (APC) bearing the T cell’s cognate peptide in an MHC molecule
What are naive T cells doing before they are activated?
they are circulating throughout the bloodstream, moving from secondary lymphoid tissue to secondary lymphoid tissue, just looking for dendritic cells to present its antigen to it
What is an HEV?
high endothelial venule; a naive T cell will have to cross the HEV wall to enter a secondary lymphoid tissue
T cells express ____s on their surface that bind to ____s onthe surface of HEV cells.
selectins; addressins
Interaction of what specific molecules initiates the “rolling” process that leads to diapedesis of T cells into lymphoid tissue?
L-selectin on T cells interacts with addressins GlyCAM-1 and CD34 on HEV cells
What is LFA-1 and what activates it?
LFA-1 = lymphocyte function-associated antigen; activated by chemokines on the HEV cell surface
What does LFA-1 bind to and what is the result?
LFA-1 binds ICAM-1; result is tighter interaction that allows the T cell to squeeze between two endothelial cells and enter the lymphoid tissue
What is the crucial factor for initiation of adaptive immune response?
the high daily rate of T cells sampling peptides presented on dendritic cells
What adhesion molecules on the surfaces of T cells bind to adhesion molecules on the surface of APCs?
LFA-1 –> ICAM-1 or -2
CD2 –> LFA-3
ICAM-3 –> LFA-1
If the T cell encounters its cognate peptide:MHC complex on an APC, LFA-1 on the surface of the T cell undergoes a conformational change that does what?
increases its affinity for ICAMs
What are the 3 types of professional APCs, and what pathogen is each specialized for?
- dendritic cells - viral and EC antigens
- macrophages - EC independently replicating microbes (e.g., bacteria and yeast) and IC antigens
- B cells - soluble antigens from IC and EC sources
What do APCs have on their surface that distinguishes them from all other cells in the body?
the co-stimulator molecule, B7
The binding of B7 to ___ on T cells is an interaction required for activation of a naïve T cell.
CD28
There are two signals that are required for T cell activation. What are they?
1) binding of the TCR to its cognate peptide in the context of MHC
2) co-stimulation signaling that results from interaction between B7 (on the APC) and CD28 (on the T cell)
Where do immature dendritic cells hang out?
under the surface epithelium and in solid organs
True or false: immature dendritic cells are very active in presenting antigen.
False - they are very active in taking up antigens
What signals dendritic cells to migrate to lymphoid tissue?
infection - recognizes a pathogen by its PRRs; takes up the antigen and migrates to a T cell center to mature and present the antigen
What’s the difference between immature and mature dendritic cells?
mature dendritic cells will express co-stimulatory molecules and high levels of MHC molecules on their surface, as well as adhesion molecules (ICAM-1 & -2, LFA-1 & -3); mature cells also produce a chemokine DC-CK for attracting naive T cells
What is DC-CK and what does it do?
it’s a chemokine (chemotactic cytokine) secreted by mature dendritic cells that attracts naive T cells
What are immature dendritic cells of the skin called?
Langerhans’ cells
**not to be confused with Langhans cells, which are multinucleated giant cells
Macrophages are scavenger cells. How do they end up presenting antigens to T cells?
they phagocytize and destroy many microbes, present the peptides on the surface. They can do this even in the absence of bacterial products (non-infectious agents)
How much MHC class II and B7 is expressed by resting macrophages?
not very much - very low levels of MHC class II and no B7
What happens to the levels of MHC class II and B7 on the surface of macrophages when they take up and process microorganisms?
MHC class II and B7 expression is upregulated for facilitated antigen presentation
How do macrophages participate in peripheral T cell tolerance?
when they encounter antigen in the absence of bacterial products they will take up and express peptides at low levels, but they will still not express B7. This results in T cell recognition of the MHC:peptide complex, but without co-stimulation so the T cell is anergized instead of activated
After binding an antigen, B cells will ____ and ____ the antigen, then present the peptide on MHC class __ molecules.
internalize and process; MHC class II
True or false: B cells constitutively express low levels of MHC class II molecules and high levels of B7 co-stimulator molecules.
False - they constitutively express HIGH low levels of MHC class II molecules and LOW levels of B7 co-stimulator
A T cell that recognizes its specific antigen bound to MHC, but does not receive the co-stimulation signal, will become ____.
anergic
Co-stimulation of the T cell in the absence of specific antigen will have what effect?
no effect…wah wah.
Activation of a CD8+ T cell by an APC other than a dendritic cell requires what?
that both the CD8+ and a CD4+ T cell must recognize antigen on the APC simultaneously. This is a mechanism of increased co-stimulation that is needed to activate the CD8+ T cell because it’s so destructive.
What makes dendritic cells special in activating T cells?
dendritic cells have intrinsically high so-stimulation activity which is significant enough to meet the threshold of CD8+ co-stimulation activity
What is the role of IL-2 in T cell activation?
- it is produced by T cells upon activation
- T cells express a receptor with moderate affinity for IL-2, but activated T cells express a high-affinity form of the IL-2 receptor so they can bind better to lower concentrations of it
- T cells binding IL-2 via the high affinity receptor allows it to proliferate 2-3 times per day for several days
What’s the difference between the lower and the higher affinity IL-2 receptors?
the lower affinity receptor has only a beta and a gamma chain, whereas the higher affinity receptor has a beta, gamma, and alpha chain
What is an armed effector T cell?
It’s what Komron would be if he were an immune cell.
LOLOL- also a fully differentiated T cell that is ready to perform its effector function. Requires no co-stimulation.
But for real, what is an armed effector T cell?
it’s a T cell that can produce all of the proteins that are required for its specialized function, they require no co-stimulation, they express higher levels of adhesion molecules LFA-1 and CD2, lose L-selectin because they no longer need to recirculate, and they express VLA-4 (adhesion molecule)
Activated T cells differentiate into effector T cells after how long?
about 4-5 days of rapid proliferation the activated T cells will differentiate into effector cells, and are then able to respond to antigen without co-stimulation
What are the 3 primary classes of effector T cells?
- Effector CD8 T cells, aka cytotoxic killer T cells
- Type I helper T cells, aka Th1 CD4 cells
- Type II helper T cells, aks Th2 CD4 cells
What is the main function of cytotoxic killer T cells?
to recognize MHC I-bound peptides presented on the surface of infected [nucleated] cells and kill them
What is the main function of Th1 CD4 cells? (Type I helper T cells)
involved in the cell-mediated immune response (intracellular infections); recognize peptides in the MHC II complex on macrophages or B cells
Type I helper T cells produce ____ that stimulate ____ and ____ cells.
cytokines; macrophages and B cells
Cytokines from what kind of effector T cells influences class switching and initiates somatic hypermutation in B cells?
Type I helper T cells
What is the main function of Th2 CD4 cells? (Type II helper T cells)
involved in the development of the humoral immune response (extracellular infections)
Th2 CD4 cells recognize antigens bound to MHC class ___ molecules presented on the surface of __ cells (primarily). They then supply _____ that influence class switching and induce somatic hypermutation.
MHC class II; B cells; cytokines
True or false: CD8 cells emerging from the thymus will become cytotoxic killer T cells, and CD4 cells are undecided when they leave the thymus.
True dat.
Th0 CD4 cells can become ___ or ___ cells.
Th1 or Th2 cells
IL-2 and IFN-gamma tend to cause a Th0 cell to become a Th_ effector T cell.
1
remember: I from interleukin and I from interferon and 1
IL-4 and IL-6 tend to cause a Th0 cell to become a Th_ effector T cell.
2
remember: 2-4-6
Name two important factors in the decision of a Th0 cell to become either a Th1 or Th2 effector T cell.
- cytokine environment
2. nature and amount of antigen presented
TH0 cells that are presented with low affinity or low concentration of antigen to the TCR tend to differentiate into TH__ cells, while TH0 cells that are presented with high affinity or high concentration of antigen to the TCR tend to differentiate into TH__ cells.
2; 1
*logic: intracellular infections will have lots of pathogen within the cell, that creates a high concentration and thus TH1 differentiation is favored in this environment
What are the 3 characteristics of T regs?
- self antigen specific T cell receptors
- CD25 expressed on surface
- transcriptional repressor called FoxP3
Th0 cells differentiate into Treg cells when they are in the presence of ____. This occurs during ____ development and is antigen-____.
TGF-beta; thymic development; independent
What happens when Tregs recognize their cognate self antigen?
they produce anti-inflammatory mediators, cytokine IL-10 and TGF-beta
Deficiency of FoxP3 results in what?
fatal autoimmune disease directed at a variety of host tissues; gut almost always affected, and other common targets are thyroid, pancreatic beta cells, and the skin
Th17 cells are a recently discovered subset of T helper cells that produce what interleukins?
IL-17, IL-22, and IL-21
A newly discovered subset of helper T cells that produce TGF-β, IL-10 are ____ cells.
TH3 cells
Selectins bind to ____; and integrins bind to the ____ superfamily members.
addressins; immunoglobulin
An addressin known as sulfated sialyl-Lewis X is also called ____ and binds ____.
GlyCAM-1; L-selectin
One interaction that can occur between naive T cells and HEV endothelial cells is chemokine recognition. When T cell chemokine receptors bind chemokines on the endothelium, what happens within/to the naive T cell?
signaling is transduced to the nucleus of the naive T cell and integrins known as LFA-1 on the T cell surface are activated, leading to increased interaction with the endothelium
Activated LFA-1 binds with relatively high affinity to what on the endothelial cells surface?
ICAM-1
L-selectin on the naive T cell surface can bind what on the surface of HEV cells?
either GlyCam-1 (aka sulfated sialyl Lewis X) or CD34
Activated T cells express the integrin ____ which can bind to ____ expressed on activated endothelial cells (activated because they are in an inflamed tissue).
VLA-4; VCAM-1
remember: v in activated) (<–that may or may not be a stretch…
In the naive T cell - dendritic cell interaction, ___ on T cell surface binds ____ on the DC surface.
LFA-1 on the T cell binds ICAM on the DC
If each individual adhesion molecule interaction has only a moderate affinity, how do T cells and APCs interact strongly enough to adequately sample the antigen?
Avidity: there are many copies of the adhesion molecules interacting for the antigen, and their combined strength is enough to cross the threshold; then the antigen binding causes a conformational change in LFA-1 that increases affinity for its ICAM
After thymic development, what is the “back-up” mechanism that recognizes and removes most self-reactive T cells from the repertoire?
the need for B7 co-stimulation; if a T cell recognizes it cognate peptide in the circulation, it will bind, but if there’s no co-stimulation along with it then the T cell will become anergic and die
What happens when a macrophage takes up both pathogen and self protein?
The proteins will be presented on MHC molecules, and the presence of the pathogenic protein pieces (recognized by PRRs) will upregulate B7. This will enable any self-reactive T cells to bind the self-protein, get co-stimulated because B7 is now present, and become activated against self proteins. Hence the belief that most autoimmune diseases are initiated during infections with a pathogen. This is also similar to the function of a vaccine.
What are the transcription factors that drive expression of cytokines in effector T cells Th1, Th2, and Tregs?
- T-bet in Th1 cells
- GATA-3 in Th2 cells
- FoxP3 in Tregs
What are the major cytokines expressed by effector T cells Th1, Th2, and Tregs?
- IL-2 and IFN-gamma in Th1 cells
- IL-4 and IL-5 in Th2 cells
- TGF-beta and IL-10 in Tregs
What facilitates neutrophil movement in between vascular endothelial cells and into inflammatory sites? (*double check this question with the podcast)
PECAM-1 and …?
What adhesion molecule expressed on naive T cells is the most important facilitator of interactions with antigen-presenting cells? Which is the important molecule on activated (effector) T cells?
LFA-1; VLA-4
What is CD34?
addressin located on the surface of HEV cells that binds to L-selectin on the surface of the naive T cell
True or false: there is no cross-over in function between Th1 and Th2 cells. (*double check this question with the podcast)
False - keep inm in that they both perform each other’s functions, specifically providing secondary signals to B cells, but it’s a matter of majority and bias
Which T cell type has a role in recruitment of neutrophils to infected tissue? (*double check this question with the podcast)
Th17 T cells are chemotractive for neutrophils
Where do Tregs reside, and how do they perform their effector functions? (*double check this question with the podcast)
secondary lymphoid tissues; they produce TGF-beta, cytokines, and other things
How do Hassall’s corpuscles lead to the production of Tregs? (*double check this question with the podcast)
they express thymic stromal lymphoprotein (TSLP) which acts on medullary dendritic cells, inducing upregulation of B7 and likely production of cytokines,
Once the two required signals for T cell activation have been received, what is/are the most important product(s) that begin to be produced by that activated T cell?
IL-2. Initiates T cell proliferation.
