Immuno lec 15, T cell activation part 1
how is the costimulatory signal received by Naive T cell? What is the ligand used to express the costimulatory signal on activated APC?
CD28 (die off at old age) B7-1 and B7-2
CO-RECEPTORs of T cells
CD4/CD8 co receptors send ACTIVATION SIGNALS INTO THE TCELL. *CD3 complex is there to transmit activation signals into the Tcell also They bind to the MHC on a different site than the peptide binding site Co receptor function is to help transmit the signal
What surface molecules on T cells suppress it?
CTLA-4 PD-1
Would we ever want to block CTLA-4?
CTLA-4 inhibits activation to self antigens but in cancer patients we want to destroy our self antigen cells if we block CTLA-4 we can recognize and kill the cancer cells
Why is the dendritic cell the most effective antigen presenting cell in a primary immune response
DENDRITIC CELL THAT PRESENTS THE ANTIGEN WITH HIGH LEVELS OF COSTUMULATION
What does LFA-1 on the surface of T cells bind to?
ICAM-1 on the surface of APC (the ligand) *the integrin LFA-1 has to be converted from a low affinity to a high affinity Naive T cells - have LFA-1 in the low affinity, once antigen binds - conformational change to high affinity LFA-1. It can now bind strongly to APC ICAM-1 Activated APC is producing Cytokines (IL-12) that also activate the high affinity LFA-1. Remember: neutrophil has LFA-1 and endothelium has ICAM-1
What is the CD28 like molecule expressed by CD4 T cells that help B cells in the follicles (follicular helper T cells)
ICOS
First action of effector T cells is proliferation, what cytokine promotes this?
IL-2, Growth factor secreted by effector T cell So an activated T cell will produce NFAT to produce IL-2
What is the significance of costimulatory molecule signal (B7-1 or CD80/B7-2 or CD86)
It is only expressed in response to a microbe and not self antigen
Activation of T cells require what two signals?
MHC-peptide-APC (antigen recognition) Costimulatory
Do effector cells or T cells at the site of infection need costimulation to be activated?
No They're specific antigen is already there and they can turn themselves on ;)
MHC-peptide-APC presentation but no costimulatory equals
No T cell response
Do vaccines activate costimulatory molecule signal (B7-1 or CD80/B7-2 or CD86) or Toll like recepors?
No, bc they are pure proteins, not microbes Solution: mix the pure proteins with ajavent to stimulate the APC to induce costimulatory molecule signal (B7-1 or CD80/B7-2 or CD86) or Toll like recepors?
Factors that impact T cell activation
Number of TCRs that get engaged by Ag/MHC (full T cell activation requires the engagement of 2 or More TCRs) Length of engagement - at least several minutes of TCR engagement are required to generate enough biochemical signals to activate a T cell response
function of CD3 in T cell activation
signal transduction
How do Ab handle Antibodies
Opsonin -tags them for phagocytosis by phagocytes or activation of complement system humoral immunity
Where does T cell activation occur
Peripheral lymphoid organs *from the blood, there are naïve T cells entering into the lymph node through the HEVs that are headed towards the paracortical area to meet up with the dendritic cells
Activation of T cell without costimulation and what is the result of this?
Recognizing self antigen No activation of PRRs thus no costimulation Result: T cells becomes unresponsive to further antigenic stimulation (this unresponsiveness is called anergy). It becomes an anergic T cell. The anergic cell may survive for days or weeks in an unresponsive/ quiescent state and then die. This is helpful so we dont development autoimmune disease' if the APC is picking up a non-microbial protein, it will not set off the PRRs of the APC, and the APC will not be able to express high levels of costimulation.
Activated APC turn on the expression of costimulatory molecule signal (B7-1 or CD80/B7-2 or CD86). T or F
T
MHC restriction
T cell receptor recognizes MHC molecule and antigen the Tcell recognizes the peptide in the context of the MHC molecule.
What interactions occur between the APC and T cell
TCR and MHC Class is the most obvious interaction taking place but it is definitely not the only one. There also needs to be costimulatory molecules AND there needs to be some adhesion between the two cells.
CTLA-4 Blockade enhances Tumor-Specific Immune Responses. WHY?
We can recognize the tumor antigens and try and combat them with T cells but the CTLA-4 steps in and says hey! this is our self antigen and shuts down the production Bad part: causes some peripheral tissue damage
intracellular virus are best handled by
a CD8 cell will kill the infected cell cellular immunity
what changes do APC make when they get activated by microbe that helps them bind to T cells
they turn on expression of costimulatory molecule signal (B7-1 or CD80/B7-2 or CD86)
Function of CTLA-4 and PD-1
binds to costimulatory molecules and inhibits activation of T cells (opposite of CD28) CTLA-4 binds to B71 and B7-2 PD-1 binds to PD-L1 and PD-L2 use them to supress responses to self antigens And when it is used when the immune response is complete and you need to shut down the response to antigen
what route does APC use to go to the lymph node?
dendritic cell is picking up antigen from the infection & carrying it down to the lymph node via the afferent lymphatic.
Appraise the physiological significance of costimulation, and recall the most significant ligand-receptor pairs in costimulation and regulation of the T cell response.
it is the second signal needed for T cell activation CD28 is expressed on Naive T cell surface that receives the costimulatory signal Only activated APC provide/express the costimulatory molecule signal (B7-1 or CD80/B7-2 or CD86)
What occurs right as the dendritic cell meets the T cell in the lymph node?
*once the Tcell gets everything it needs from the APC, there are growth factors produced BY the Tcell, that will now promote the expansion of the Tcell; clonal expansion will build up the number of cells that are specific for that particular antigen.
intracellular microbes are best handled by HELP, is this correct to say
macrophages that are activated by CD4 cellular immunity
3 different ways that you can get the activation of your CD8 T cells HELP - che
3 different ways that you can get the activation of your CD8 T cells 1. CD8 T cell recognizes antigen that is being presented by an antigen presenting cell that itself has high level of co-stimulation (no help from CD4) (cross presentation - APC going MHC class I route) 2. CD8 T cell is recognizing antigen, but at the same time is getting help from CD4 T cell (stimulation from CD4 T cell By way of cytokines, IL-2 , to proliferate CD8 cells) 3. CD4 T cell recognizes antigens represented from APC and that CD4 T cell will help APC and that will turn on expression of Co -stimulatory cell on APC and APC can go present antigen to activate CD8 T cell with costimulation
what is the accessory molecules
molecules for adhesion (LFA-1, integrin) and signaling Also costimulatory molecules, CD28 on T cell surface *ALL OF THE MOLECULES INVOLVED IN THE T CELL RESPONSE OTHER THAN THE ANTIGEN T CELL RECEPTOR ARE CALLED ACCESSORY MOLECULES the Tcell receptor is different from cell to cell, BUT ALL THE ACCESSORY MOLECULES ARE THE SAME. *same accessory molecules will be used regardless of the antigen specificity of the Tcell
interactions between T cell receptor and APC
Adhesion(LFA-1, integrin) : we need to strengthen the interaction between the APC and the Tcell Signaling: there needs to be signaling information transmitted into the Tcell in order to get it activated Antigen Recognition
What do you think would be the result if an individual had a loss of function mutation in the gene for CTLA-4 of PD-1?
Autoimmune disease develop
Extracellular microbes are best handled by
B cells humoral immunity
Why do T cells need so much activation?
Bc we selected T cells that have low affinity to antigens best way to overcome it - LFA-1 integrin - adhesion molecule *THE INTERACTION BETWEEN THE LFA-1 AND THE ICAM IS WHAT WILL INCREASE THE AFFINITY BETWEEN THE TCELL AND THE APC.