Cell-Mediated Immunity (Lecture 5) Flashcards
Cell-Mediated Immunity
-Recognition of Antigen by T Cells
YA
Recognition Of Antigen By T Cells
B cells utilize ____ as their cell surface antigen receptor and can therefore recognize soluble antigens as they exist in their native conformation.
Do T cells utilize a molecule similar in structure and function to antibodies as an antigen receptor?
antibody
Recognition Of Antigen By T Cells
A major mechanism through which viral infections are eliminated is via ____-mediated killing of infected cells.
Cells infected with replicating viruses express virally-encoded proteins in their native conformation on the outer aspect of their ____.
How do cytotoxic T cells recognize virally infected cells and subsequently kill them?
T cell
plasma cell membranes
Recognition of Antigen by T Cells
Zinkernagel and Doherty: How do the CTLs specifically recognize LCMV-infected target cells?
Hypothesis: CTLs have receptors that interact directly with intact ____ proteins on the surface of infected target cells; engagement of the receptor leads to killing of the target cell.
viral
Zinkernagel and Doherty Experiment
Chromium Release Assay
take target cells and incubate them in media that has radioactive ____ in it (the isotpe = 51); the cells will passively take up Cr51 intracellularly and keep it within the cytoplasm
then, take the radioactively labelled target cells and mix them with a hypothetical population of killer cells; prior to interaction of activity bt target and killer cells > everythings been sequestered by target; all of the radioactivity is associated with the ____ cells
incubate target cells for 6 hours, killer kills some of targets, the Cr51 is released into the ____ (run through a scintillation counter) > you start to radioactivity in the media
amount of radiation found within the media is directly related to the number of ____ that have been killed by killer T cells
strain A mouse, inject it with LCM virus > induce a response (bc adaptive immune response)
week later, boost the animal again, then isolate the T cells (cells from spleen, lymph nodes, or both) > utilize the assay (incubate with killer cells and cells of different type (uninfected and infected))
chromium
target
media
target cells
Zinkernagel and Doherty Experiment
no killing, bc the response that we’re inducing has ____ to it (must be LCMV specific, with the proteins)
proteins expressed on the strain B is the same as the proteins expressed on the strain A
if proteins are expressed, but on a different cell type > no ____
specificity
killing
Conclusions:
- CTLs must recognize ____ molecules and ____ MHC molecules of the
infected strain on the surface of a target cell in order to kill it.
- MHC molecules do not function solely as alloantigens that mediate graft rejection but more importantly have a role in recognition of ____.
Concept of MHC Restricted Recognition of Conventional Antigens by T Cells
CD8+ cytotoxic T cells recognize peptides bound to self ____ MHC molecules.
CD4+ helper T cells recognize peptides bound to self ____ molecules.
viral
conventional (microbial) antigens
class I class II
How can MHC restriction be explained in the context of an antigen receptor?
Dual Recognition Hypothesis:
- CTLs have two distinct antibody-like receptors on their cell surfaces that must be
engaged ____ in order for the target cell to be killed; one for ____ antigen and the other for a ____ molecule.
Altered Self Hypothesis:
- CTLs have a single antigen receptor that recognizes a ____ molecule modified
by viral molecules.
simultaneously
viral
self-MHC
self-MHC
The T Cell Antigen Receptor
So this the ____ form of the antigen receptor. They are two ____ pretty much the same size. They both have ____ and ____ domains. They both have variable and constant regions. The variable regions make up the amino terminal half of the alpha beta chains, and the constant regions make up the carboxy terminal halves of the alpha and beta proteins. So in some ways what does this look like? Answer: Almost half of an ____ molecule. Yet it doesn’t behave or function in a manner that closely resembles the way antibody molecules do.
alpha beta glycoproteins transmembrane cytoplasmic antibody
The T Cell Antigen Receptor
The other series of proteins that I want to point out to you at this point are over here (on right), and it is actually a family of proteins that aggregate with one another to form a molecule or structure that is referred to as ____. Remember I told you that this is the ____ cell marker. CD3 is composed of epsilon chains, delta chains, gamma chains, and what are referred to as ____ chains. And the function of CD3 is to act as a mechanism for ____ signal transduction once the antigen receptor has engaged whatever it is it’s specific for. So CD3 has nothing to do with dictating the ____ of the T cell. It functions as a mediator of ____.
CD3 pan T zeta amplifying specificity signal transduction
The T Cell Antigen Receptor
So how does this thing work? What they recognize are peptides derived from those proteins in association with self MHC molecules. The self MHC associates with the ____ derived from, for example, a viral protein.
They recognize peptides derived from those proteins associated with ____ molecules on the surface of the target cells.
peptide self class I
Comparison of the B and T Cell Antigen Receptors
But again, it will not recognize proteins in their native conformation, which antibodies are fully capable of doing. T cells require that the protein be denatured ____, resulting in the generation of peptides that are then expressed on the surface of the target cell in association with self class I molecules. And that is something that the T cell antigen receptor can bind to. So at this point, I’m not really interested in you understanding how the peptides are generated and how they get on the cell surface. But just the concept that the antigen receptor has to interact with a peptide and a self class I if it’s a ____, T cell or self class II molecule if it’s a ____ T cell.
intracellularly
CD4+
CD8+
Recognition of Antigen by T Cells
interacts with the complex formed by the ____ peptide and the ____ molecule > serves as activation (engagement of antigen receptors, and secondary signals derived from other cells)
upon binding, initiates apoptosis on target cell and ultimately kill it
the strain A nucleated CTL (killer) cell also have ____ molecules, even the killer cell can be targeted and destroyed
viral self class I self class I
Zinkernagel and Doherty Experiment
no infection, peptides are derived from ____ proteins (shows self, uninfected); t-cells do not recgonize these peptides
and then in the last scenario, there is a cytotoxic T cell coming from a virally infected animal, now mixed with a strain B LCMV infected target cell. They’re over here, but the fact that it’s not the appropriate ____ molecule, the T cell can’t recognize this complex and leaves it alone.
cellular class I (allogeneic MHC)
Recognition Of Antigen By T Cells
- T cells are specific for ____ sequences of discrete peptides; not intact soluble proteins.
- T cells only react against foreign peptides when they are attached to the ____ of another cell (antigen presenting cell).
- T cells from any one individual will only recognize foreign peptides when they are complexed with the ____ molecules of that individual.
amino acid
surface
class I/II
Recognition of Antigen By T Cells
So how do these complexes form? So we have to go back and appreciate the structure of class I and class II molecules. We talked about the fact that they have binding clefts and now you know that what fits into these binding clefts are ____. Different class I molecules will bind different sets of ____. Different class II molecules will bind different sets of ____.
peptides
peptides
peptides
Recognition of Antigen by T Cells
And you as an individual have the class I molecules you inherited from your ____ and your ____. So that gives you, I’d have to do the math, but that probably gives you ____ different types of class I molecules.
And then you have the genes encoding class II molecules that you inherited from your mother and your father. And there’s thought that the alpha and beta chains from the mother and father can actually associated with one another so that there can be ____ class II molecules produced. So that gives you, again I’d have to do the math, on the order of ____ class II molecules on the surfaces of your cells.
So it’s not a huge number, but it’s sufficiently large enough that you can take peptides from a ____ number of microbes and show them to T cells.
mother
father
10 or 15
“hybrid”
20 or 30
huge
Antigen Presenting Cells
The responses of antigen-specific T cells require the participation of accessory cells that “capture” the antigen, process it into ____ fragments that are then displayed on the cell surface in association with a ____ molecule. Collectively, the cells that perform this function are know as ____.
____ are the only antigens that can be processed and presented to T cells!
Things have changed a little bit, so that the term antigen presenting cell, in a very generic sense, can be either a ____ or a cell that processes and presents an antigen in a context of ____ molecules.
peptide
MHC
antigen presenting cells
proteins
target cell class II
Antigen Presenting Cells
All ____ cells express class I MHC molecules and therefore can process and present antigens to ____ cytotoxic T cells.
Only the limited number of cell types that express class II MHC molecules can also act as ____ for CD4+ helper T cells. These unique cells are referred to as ____ antigen presenting cells.
nucleated
CD8+
antigen presenting cells
“professional”
Professional Antigen Presenting Cells
Main Functions
____ – presentation of antigen to naïve T cells and initiation of responses to protein antigens.
____ – effector phases of cell-mediated immune responses.
____ – presentation of antigen to CD4 T cells in humoral immune responses.
dendritic cells
macrophages
B cells
Antigen Processing and Presentation
Cytosolic proteins are typically synthesized within the cell and include: - \_\_\_\_proteins - \_\_\_\_ proteins - intracellular bacterial, fungal and parasitic proteins - mutated \_\_\_\_ (tumors)
Occasionally, peptides derived from microbes and other exogenous antigens can enter this pathway by passing from a ____ into the cytosol.
Class I, or Class II pathway
Class II: the protein that is processed and presented comes form outside the cell (macropinocytosis, pinocytosis, RM endo, or phago); the antigen is ____ to the cell itself
Class I (self): biosynthesized ____ the cell itself, the proteins are endogenously derived (our own, proteins encoded by viruses, intracellular bacteria, and protozoa)
self
viral
self proteins
phagosome
exogenous
within
T Cell Activation
Similar to B cells, activation of T cells requires ____ signals.
These come in the form of:
• a primary signal derived from the binding of the ____ by the T cell receptor
• secondary signals that are provided by ____ molecules expressed on the the surface of the antigen presenting cell as well as ____.
So on the surface of the antigen presenting cell is a self class II molecule with a peptide associated with it, a configuration that the T cell antigen receptor can interact with. The other molecule that you’ll see is the CD4 molecule. I’m going to say this and I hope it doesn’t confuse you: the CD4 and CD8 molecules bind to non polymorphic components of either class II or class I molecules. So CD4 binds to a portion of class II molecules that is ____ in all of us. CD8 binds to a non polymorphic component of class I molecules that is ____ in all of us.
The secondary signals, which in this diagram are represented by the green arrow, are ____ signals that are derived from the interaction between receptors and ligands on the surfaces of the antigen presenting cell and the T cell, as well as from ____ that are released by the ____ and binding to specific receptors on the T cell. Analogous to what we saw with B cells.
peptide:MHC complex
co-stimulatory
cytokines
identical
identical
co-stimulatory
cytokines
antigen presenting cell
T Cell Activation
And then when all of that happens, we end up with this signal transduction cascade that ultimately leads to the activation or expression of ____, which find their way into the nucleus and then induce the expression of genes encoding proteins that are required for initially the ____ of of the T cell, and then secondarily the ____ of the T cell.
transcription
proliferation
function
T Cell Activation
REWATCH
helper t cells produce ____ themselves; they also express the genes for the ____; ____ form of growth regulation
IL-2
IL-2R
autocrine
