Immunology: Midterm; Lecture # 4

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1. Antigen Processing and Presentation: A. MHC Basics

outline

Antigent Processing and Presentation: Recall: T cells don't recognize native (unprocessed) antigen , they recognize

Peptide fragments in MHC molecule

MHC =

Major Histocompatability Complex (i.e. hotdog bun that presents hotdog which is antigen

MHC complex is a ___& ____ chain plus a ____

Alpha & Beta; Peptide

The MHC is a ___ helix on either side with ___ pleated sheets down the middle

Alpha; Beta

MHC size = ___ # AA's

9

The T cell receptor sits on the MHC at a ___ degree angle so it can touch both ___ and ___ at the same time

45; MHC/Peptide

There are two classes of MHC- the biggest difference between class 1 and 2 is

the size of the bun

Peptide is bound in groove cause side chains interact with

Beta pleated sheets

2. MHC Expression: every cell in your body has ____ on it

MHC

Once MHC is on the cell surface; this is what activates ____ cells

T

It takes as few as ___ MHC cells (identical) with 1 kind of peptide to activate a T-cell ; This # is the bare minimum however and typically it takes ____

3; 50
3-50 out of (1,000-2,000)

On the surface of any cell you will have variety of ____ and a variety of ______ in them

MHC; peptides

The T-Cell must recognize ___ identical MHC molecules and with ____ identical peptides to get activated

50;50

T-Cell will recognize stuff that was ___cellular

Intra
* this is directly in contrast to Antibodies which recognize stuff that was Extracellular

3. Advantages to MHC presentation: T-cell can be specific for a peptide that's buried in a protein, whereas _____ can't usually reach these epitopes

Ab

Advantages to MHC presentation: T-Cells can respond to ______ pathogens, whereas Ab's only to ______

T-cells; Intracellular
Ab's ; Extracellular

B. MHC Class 1 Pathway: MHC class 1 is found on

All Cells

MHC Class 1 Pathway: Cell infected by Virus- defined for viruses, but it happens for all cell & Self Proteins if

no virus present

1. MHC Class 1- The Pathway: First, the Cell get's infected by

Virus

Next, the cell makes the viral proteins along with self proteins : this is called

Endogenous Antigens

If the viral proteins reach the Cytoplasm , they are now called

Cytoplasmic Antigens

Cell doesn't want that protein in Cytoplasm , so protein is _________ and target for degradation by the _____

Ubiquitinated; Proteasome

The Proteasome looks like

A stack of Tires
*Protein fed down middle and out the other side comes Peptides (like Lumbar mill will wood in and sawdust out)

Proteins come out that are __ to __ # AA's in length

8-10

Meanwhile, new Class 1 is being made in

ER

Need to get ______ onto class 1 being made in ER

Virus Peptides

Peptide is transported by ______ into ER , where it binds to newly synthesized class 1 MHC

TAP (Transporter of Antigen Processing)

MHC buds off the ER in an ____ with ____ bound

Endosome; peptide

MHC goes to

Cell Surface

MHC class 1 + Viral Peptide is recognized by ____ cells

CD8 T-cells

This pathway was originally described for virus, but then realized that bacteria use it too as long as they're inside cell . Now it's called the _____ pathway

Endogenous

Overview of Endogenous Pathway:

1. Bacteria makes Protein ; Protein gets fed thru Proteosome and Peptides come out the other side

2. Peptide gets transported thru TAP into ER, where it binds to MHC class 1 molecules

3. Bud off the ER ---> go to surface

4.CD8 T-cells check it out

C.) MHC Class 2 Processing Pathway; "The Exogenous Pathway" : MHC Class 2 molecule only found on

"Professional" Antigen Presenting Cells (APC)
Originally defined for exogenous bacterial toxins, but works for self as well

Examples of "professional Antigen Presenting Cells (APC) =

B cells, Macrophages, and Dendritic Cells

MHC Class 2 Pathway (the Exogenous pathway): is for a bacteria or toxin that is

Outside the Cell

Class 2 Pathway: The cell takes up the bacterial through ___ or ____ so now it's Inside the cell

Endocytosis; Phagocytosis

Coming from ER first there is Lysosme with MHC class 2 inside and ______ is blocking the peptide binding groove

Invariant Chain (Ii)

The _____ and ____ fuse and all the enzymes start busting up the bacteria

Endo/Phagosome; Lysosome

MHC 2 in the Lysosome binds with

Phagosome

____ gets degraded and the ____ takes it's place

Invariant Chain (Ii); the Peptide

The MHC class 2- Peptide Complex is transported to ___ where it gets recognized by ____

the surface of the cell; CD 4 T-cell

D.) The Third Pathway: Superantigen : Superantigens don't have

Processing Pathway

APC's express both

MHC class 1 & MHC class 2

T-Cell receptor which is specific for

certain Peptide

Superantigen links The ___ & the ____ together NONSPECIFICALLY

T cell; APC

___ binds OUTSIDE _____ and NONSPECIFICALLY activates T cells

SAg (Superantigen) ; Peptide Binding Groove

When this happens (see previous quest) it can activate __ to___ % of all your T cells at the same time and is very TOXIC

2-20 %

Superantigens can be made by ___ or ___

Virus or Bacteria

Most famous Superantigen is

TSST (Toxic Shock Syndrome Toxin)

TSST is made by ___ in the ___

S. aureus ; Vagina

TSST-1 glues T cells to _____

APC's

TSST: T-cell spits out tons of ____

Cytokines

TSST: The activation of __ % of T cells at once is toxic (too many)

20 %

Cytokines =

Fever, Nausea, Vomiting, Myalgia (muscle pain)

TSST: the bacteria doesn't kill the person , rather ___ does

The overactivation of the T cells

TSST: 50% of people go into __ or ___ failure

Kidney; Cardiac

Another Superantigen example is:

SEA and SEB (Staph enterotoxin A & B)

SEA and SEB are responsible for

Food Poisoning

Staph enterotoxin gives you the following symptoms:

Diarrhea, fever, nausea, vomiting, myalgia and severe headaches

2.) MHC Polymorphism: MHC is a protein that makes

you , you! :)

A.) Difference in Alleles: There are many different ___ for MHC

Alleles

MHC = Tissue ____

Compatability

The MHC molecule is the reason you can't put someone else's ___ into yours

Tissues

In humans, MHC is called

HLA (Human Leukocyte Antigen ) , meaning it was on White Blood Cells

Have a series of Genes: Class 1

HLA, HLB, HLA-C (one from mom, one from dad = total 6)

Class 2:

HLA-DQ, HLA -DR, HLA-DP (= total 6) = Grand total of 12

Each of the classes of molecules is made up by a ___ and ___ chain so each 1/2 of hotdog bun made by different genes

alpha/ beta

There's ____ # different versions of DP overall... but___ per person

150; 2

Highly Polymorphic and typically people are _____ a each Locu

Heterozygous

MHC expressed as _____ not allelic exclusion, meaning that both alleles ??(notes incomplete)

Co-Dominance

Alloreactivity: occurs during

Organ Transplant- when you get graft rejection

Alloreactivity is when T cells respond to a _____ MHC

Non-self

Studies have tried to determine if the peptide is important during an alloresponse but they are inconclusive; sometimes the peptide is important, sometimes it isn't . Alloresponse is due to ____ and Allo= ____

Opposite MHC; Difference

Allografts are when that first T-cell question____ is important

Are you Me?

T cells decide if that MJC is you, and if it isn't they get _____

Activated

Xenograft uses ___ tissues

Animal

Xenograft is away around

Alloreactivity

Xenograft uses animal tissues for

Transplantation

Animal MHC is so different from Human MHC that T cells don't recognize it at all and can't ___ to it

bind

_____ (an animal) is the closest to human/structure and function that we can get and what's most often used in Xenografts

Pig

However, ____ cells recognize the absence of MHC and can attack Xenografts

NK (Natural Killer)

Scientists have been taking care of the NK cell attacking Xenograft problem by:

Genetically engineering pigs to express correct MHC, i.e. we are introducing human MHC into an animal so it won't reject us

New Technology: Tissue Regeneration: Advantages

-Uses person's Stem Cells
-Grows tissue around a model

New Technology: Tissue Regeneration: very important part is

-Connective Tissue/ Extracellular Matrix

Development of T cells: TCR structure

-Doesn't look like Antibody- only one antigen binding site
-Still has variable regions and constant regions

TCR Recombination:

-Genes rearrange like Antibody genes
-Has VDJ gene rearrangement, except that there is no D- just V and J on both alpha and beta chains; T cells have N-Nucleotide addition for more variation
-No Somatic Hypermutation
-Receptor Editing-looks like it happens in mice; no evidence in humans

Alpha/Beta T cell Receptors

-Recognize MHC + Peptide
-Travel thru Lymph node looking for the antigen
-Goes thru Thymus during development
-Specific - I cell per 1 Antigen (i.e. 1 Peptide)

Gamma/Delta T cell receptors

-Recognize whole antigens (like Ab) ; this is what tells us that more prehistoric than alpha beta
-They go directly to site of infection or mucosal tissue; not thru thymus or lymph nodes
-These are the only T cells you find in tissues in absence of Immune Response
-More innate; it's like they are recognizing a pattern
-Evolutionary, they predate alpha-beta cells

CD4 and CD8 T Cells

-Precursor T cell leaves Bone Marrow and travels to Thymus
-At the time they reach the Thymus, the T Cells have both CD4 and CD8 on their surface and are called Double Positive (DP) T cells
-(+) for both CD4 & CD8
-The T cell at this point has no idea what its specific for
-Thymus is encapsulated and there's a mesh of cells that act like strainer
-This mesh of cells is Thymic epithelium and Dentritic cells expressing MHC 1 and MHC 2
-DP T cells enter Thymus and drop into the mesh
-If TCR binds to MHC class 1 in the thymus, it becomes CD8 T cell; If TCR binds to MHC class 2 in the Thymus, it becomes a CD4 T cell; The T cell downregulates the receptor that they aren't going to be (i.e. CD8's downregulate CD4 and vice versa)
-Here they are single (+)

2 Kinds of T cell Tolerance

-Central Tolerance
-Peripheral Tolerance

Central Tolerance

- While the T cells are in the Thymus, they figure out what "self" is
-They decide to be CD4 or CD8 based on the MHC, they look at the Peptide
-Three possibilites for the T cells at this point:
1. Don't recognize anything (DUD) = Death by Neglect
2. Strongly bind to MHC + Peptide Self = Negative Selection =Active Death
3. Bind MHC but not the Peptide = Positive Selection = Live!

Peripheral Tolerance: T cells that reach the Periphery should be tolerant to self, the problem is

Not all Self Antigens are expressed in the Thymus
(for example; Insulin not made by Thymus so T cells can still respond to Insulin)

Solution: Peripheral Mechanisms to keep T cells in check

Signal Hypothesis:

Signal 1: MHC + Peptide
Signal 2: Co-stimulation (CD86 on APC binds to CD28 on T cell)

Costimulation Reaction

-T cell on its surface it has TCR, CD4, and CD28

-APC has MHC class 2 + Peptide in groove and CD86
*CD86 is Key Protein b/c only expressed by professional APC when they get signal to get activated from Toll receptor and this only happens when you have an infection

-This prevents you from responding to self

-CD28 binds to CD86 and that's the Second Signal

Tolerance

Signal 1 alone= Anergy
Signal 1 + Signal 2 = Activation

*Only APC's can activate a Naive T cell and only when they receive a danger signal (CD86)

...

Effectors can be activated with Signal 1 alone

...

Study Questions: Do Hepatocytes express MHC class 1? class 2?

MHC class 1; they aren't professional APC's so no MHC 2 `

Do T cells or Antibodies respond to Extracellular Epitopes?

Antibodies ---> Extracellular
T cells ----> Intracellular

What is the protein that breaks down Cytosolic Proteins?

Proteosome

Which MHC processing Pathway uses TAP?

MHC Class 1

What is the importance of the Invariant Chain?

Ii blocks the peptide bonding groove so that no peptides bind in the ER and then degrades so that peptide can bind when the MHC class 2 molecule reaches the periphery

How does MHC polymorphism cause Allograft rejection?

Different people express different MHC's due to Polymorphism. T cells only recognize the MHC of the person that they were raised in. So T cells will reject any foreign MHC's

What is HLA-DQ ?

A class 2 molecule

Where do CD8 T cells become specific for MHC class 1?

Thymus

If you Isolate a T cell from the Uterus, what type of T cell is it likely to be?

Gamma Delta T cell

What happens if a bacteria gets into a cell without activating a TLR?

If a bacteria doesn't activate a TLR, the APC might not upregulate CD86. If no CD86, no immune response in the periphery

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