\ HLA-D\ DP -- A1, A2, B1, B2 DQ -- A1, A2, B1, B2, B3 DR -- A, B1, B2, B3

Lecture 4: MHC & Ag Presentation to TCells Flashcards by Chris Rodarte

Bare Lymphocyte Syndrome is a form of _____ caused by…

SCID

Mutations in MHC (either type 1 or type 2)

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T cell recognizes antigen via ______ molecule on an APC

MHC

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Major class 1 genes are…

HLA - A,B,C

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Minor class 1 genes

HLA – E,F,G,H,J,X

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Major Class II genes

*HLA-D*

DP – A_1,A₂, B_1,B₂

DQ – A₁, A₂, B₁, B₂, B₃

DR – A, B₁, B₂, B₃

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Major Class III genes are _________ and have _______________

Diverse

Non-antigen presenting functions

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Class ___ region of HLA are the farthest

Class I

BCE AGF

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Class ____ region is the closest on the HLA complex

Class II

DP, DQ, DR

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HLA genes that are not expressed (not funcitonal) are referred to as _______

pseudogenes

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The MHC on every human chromosome 6 contains one gene for ____ and _____

DRA

DRB1

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Any ____ chain can pair with the ____ chain to form a class II Molecule

DR-B

DR-a

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MHC I structural domains

alpha 1 + 2 + 3

beta 2

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MHC I – peptide binding site formed by _____ domains

a1 + a2

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MHC I Molecule is anchored to cell membrane by ____ domain(s)

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B2 microglobulin is ________ but __________

invariant but essential

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The alpha chain of MHC is also known as the _____ chain

heavy

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MHC II is composed of one ___ chain and one ____ chain

one alpha and one beta chain

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MHC II peptide binding site is composed of ______ domain(s)

a1 and b1

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For MHC II, which chains are variable and which are constant?

a1 + b1 are polymorphic (variable)

a2 + b2 domains are constant

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T cell structural domains:

V-alpha + V-beta

C-alpha + C-beta

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T cell antigen binding region comprised of ___ and ____ domains

V a/b

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The peptide binding groove of MHC molecules is made of about ____ peptides

8 - 15

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Rank the top three MHC I HLA’s in terms of polymorphism.

What cells do these correspond to?

B > A > C

CD8 T-cells + NK cells

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MHC class I effect on CD8+ cells and NK cells?

Activate CD8+ cells

Inhibit NK cells

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Polymorphism definition...

presence of **multiple alternative alleles** of a gene

What is, by far, the most highly polymorphic MHC II allele?

DRB1

DMA/DMB DOA/DOB These genes serve what function in MHCII

Help peptide loading O+M

DP, DQ, and DR genes provide what function for MHC II

**Present antigen peptides** to CD4+ Tcells

Polymorphism allows the human population to \_\_\_\_\_\_\_\_\_\_\_

hadle a variety of pathogens

MHC genes exhibit \_\_\_\_\_\_\_. \_\_\_\_\_\_\_ are expressed.

Co-Dominance Both alleles are expressed

In any mating, \_\_\_\_\_\_ possible combinations of haplotypes can be found in the offspring (for MHC molecules)

4 combinations

(With regard to chromosome 6) A **haplotype **is a...

particular combination of MHC alleles found on a given chromosome 6

HLA -E and HLA-G are ____ and interact with \_\_\_\_\_\_

Oligomorphic ## Footnote **NK cell receptors**

HLA-F function

Unknown. It remains **intracellular** with a **SINGLE** isotype.

Common function to HLA A, B, and C?

Present Antigen to CD8+ cells

Common function to HLA-DP, DQ, and DR?

Present antigen to CD4+ cells

\_\_\_\_ is the most highly polymorphic allele for MHC-II

HLA-DRB1

MHC class II variablity is due to the ___ domain because the _____ chain is monomorphic

**Beta 1** domain The **alpha** domain is **monomorphic **(a1+a2)

Each MHC molecule binds a characteristic set of peptides. ________ in these peptides are important for binding to MHC

Anchor residues

What is "degenerate binding"

the property which allows **each MHC** molecule to handle **many different peptides**

MHC I molecules bind mostly _____ peptides, and positions __ and __ are the usual anchor residues.

**_Nonamer_** peptides Positions **_2_** and **_9_**

Some MHC II can have mor ethan 3 isotpes because there may be more than one \_\_\_\_\_. This means a cell will have what combination?

**DR** gene **DRB1 + DRA** (like all cells) _WITH_ either *DRB3, DRB4,* or *DRB5 *

(In both MHC I and II) which are the most polymorphic

**HLA-B** and **HLA-DRB1**

\_\_\_\_ is most monomorphic HLA

HLA-**DR-α**

HLA _______ are present in only some people

HLA **DRB3, DRB4, DRB5**

Most people are ______ (genetically) and express \_\_\_\_\_\_\_\_

Heterozygotes Two Haplotypes

A person can express _____ Class I isoforms and ______ Class II isoforms.

3-6 3-8

There are _____ MHC I isoforms and _____ MHC II isoforms in the human population

753 Class I 2406 Class II

MHC\_\_ is expressed in all cells

MHC 1

These four cells are the only ones to express high levels of both MHC 1 and II molecules.

B cells MQ DC Thymic epithelial cells

These are the three APC cells

B cells, MQ, DC

\_\_\_\_\_\_\_ do not express either MHC I or II

Erythrocytes

\_\_\_ increased MHC II expression in APC's. What is the other effect?

**IFN - Gamma** it **induces** the expression of MHC II in **non-APC'**s at the sites of infection

MHC II handles ____ antigens

Extracellular

Antigen processing for MHC II (process)

* Extracellular ag **endocytosed** * **-\> phagolysosome** * MHC II in **vesicle** goes and binds Ag * MHC II **presents** the Ag at the surface

MHC Class I handles ____ antigens

Intracellular

MHC class I Antigen processing (steps)

Ag in cytoplasm is **u****biquinated** **-\> Proteosome** Transport to **ER** Bind MHC \*_in ER_\* **Presented** at surface

Intracellular Ag's are handled by _____ and they can originate from ___ (such as \_\_\_)

MHC I viruses (such as HIV)

MHC I proteins are assembled in ER and associate with ___ and \_\_\_

TAP protein Calnexin (Chaperone)

TCR's do not bind to ___ but rather to \_\_\_\_

Dont bind **whole antigens** instead bind to **antigen peptides**

Transport of peptides to ER requires

TAP **T**ransporter associated with **A**ntigen **P**rocessing

What happens when you don't have TAP protein

**Bare Lymphocyte syndrome** _No TAP _ = _No MHC1_ = _No CD8+ _ = _No Cytotoxicity_ = **Chronic Respiratory infection**

TAP is made of

TAP1 + TAP2

\_\_\_\_\_ length polypeptides are transported via TAP

8 or more amino acids

MHC1 cant ______ without peptides being loaded

can't leave ER

Three molecular chaperones that aid in MHC folding and loading of peptides:

Calnexin Calreticulin Tapasin

MHC class 1 is stabilized by ____ in ER until ____ binds

Calnexin B2

In absence of infection, _____ are presented on MHC but these \_\_\_\_\_\_\_\_

self peptides do not activate T cells

After synthesis in the ER, MHC 2 peptide binding site is protected by

**CLIP** region of **Ii ** | (Invariant chaperone)

CLIP is removed from MHC II by \_\_\_\_\_

HLA DM protein

\_\_\_\_, \_\_\_, and ____ guide the peptide loading of MHC II

invariant chain CLIP HLA-DM

What must happen after CLIP is gone?

MHC II needs to bind to peptide or it will be **degraded**

Where do MHC II bind to peptides?

In fused vesicles

CD8 ___ group binds to the ____ group on the MHC molecule

CD8 **alpha** group binds to **a3** on MHC1

CD4 binds to ____ group on MHCII

B2 group

T cell receptor recognitionof antigens is \_\_\_\_\_\_\_\_\_

MHC restricted A TCR may not recognize a particular peptide when it is bound to a different class of MHC, or a different peptide on the *same *MHC

CD8 kills virus infected cells how?

directly

CD4 T cell does what to stimulate other cells?

*Makes cytokines* **Activate macrophage** to make its own _cytokines_ **Activate B cells** (to plasma cell) to make _Antibodies_

HLA typing is dome via what methods

Microcytotoxicity Assay RFLP PCR Flow Cytometry/ELISA

Microtoxicity Assay uses ____ which is mixed with lymphocytes Exogenous complement is added which results in ....

Anti-HLA serum results in **lysis** of cells that have bound Antibody

During RFLP, DNa is digested and hybridized to

Radiolabeled MHC

PCR uses

MHC specific primers

ELISA uses

monoclonal antibodies to MHC alleles

Other test for HLA compatibility What are we looking for?

Mixed Lymphocyte Reaction test Higher response = higher the match

Disease for DR3 + DR2

SLE

Disease for DR4

Rheumatoid Arthritis

DIsease for B7 and DR2

Disease for B8 + DR3 + DR4

T1DM

Disease for B27

Ankylosing Spondylitis