6. T Lymphocytes and antigen recognition Flashcards by Georgia Leggett

Role of a T lymphocyte

Detects and combat intracellular pathogens

“Sees” foreign antigen via a receptor on its cell surface (TCR)

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What is the TCR analogous in structure to?

FAB of antibodies

“membrane bound version of FAB”

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What is the general structure of a T Cell Receptor?

Consists of an alpha and beta chain

Both chains have a variable region and a constant region

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What other receptor are TCRs associated with?

CD3:
present on all T lymphocytes
Have a longer cytoplasmic tail than the TCR

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How is CD3 important?

Signals from the TCR are transmitted to the internal compartment of the cell via the CD3 receptors
The tails of CD3 have tyrosine residues
When antigen binds to the TCR, phosphorylation of tyrosine occurs in the tails leads to many chemical cascades, activating T cell

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What are the 2 major populations of T cells?

Use CD4 co-receptor

Use CD8 co-receptor

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What class of MHC do CD4+ T cells bind to?

MHC Class II

“Class II restricted”

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What class of MHC do CD8+ T cells bind to?

MHC Class I

“Class I restricted”

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What do the CD4 and CD8 co-receptors do?

Bind to relevant MHC (conserved part, not antigenic peptide)
Increase avidity of T cell-target interaction
Important in signalling

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What do CD8+ cells do?

most are cytotoxic and kill target cells:
Secrete cytokines to alert other cells of infection
Induce apoptosis in target cell

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What are CD8+ cells also known as?

CTL

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What do CD4+ cells do?

secrete cytokines:
Recruit effector cells of innate immunity, help activate macrophages
Amplify and help Tc and B cell responses

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What are CD4+ cells also known as?

T helper cells

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Where do T cells mature?

Thymus

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Where are immature and mature thymocytes found in the thymus?

Immature: Cortex
Mature: Medulla

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Describe T cell development in the thymus.

T cells initially have no TCR or CD4/CD8 receptors (double negative)
The beta chain of the TCR assembles 1st, followed by the alpha chain: forms preTCR
If the TCR is functional, the T cell goes on to express both CD4 and CD8 receptors (double positive)
Depending on which MHC class it binds to it eventually ends up being only CD4+ or CD8+

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What allows generation of a huge number of different TCRs?

Random recombination of TCR gene segments

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What and how many recombination events for beta chain of TCR?

VDJ recombination

2 events

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What and how many recombination events for alpha chain of TCR?

VJ recombination

1 event

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What are the 2 unwanted outcomes that may arise from the random process of recombination to form TCRs?

Potential to generate TCRs that recognise self-tissue
=Autoimmunity
Potential to generate TCRs that can’t see self MHC molecules, can’t see self MHC presenting peptide
=Useless

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Thymus selection 1: PreTCR checkpoint

Is the new beta chain functional?
Yes: survive and develop
No: death by apoptosis

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Thymus selection 2

Is the alpha-beta TCR functional?

Is the alpha-beta TCR dangerous/ auto reactive?

What percentage of thymocytes survive selection?

What are the 3 main subsets of T lymphocytes?

CD8+ CTL
CD4+ Th1
CD4+ Th2

What types of TCRs cause deletion by apoptosis during deletion?

TCRs that bind too strongly (may lead to autoimmunity) TCRs that can't bind at all Need to be able to bind to self MHC, but not too strongly

What do MHC molecules present?

Sample of internal contents of cell on cell surface for possible immune recognition Present peptides, even in absence of infection

What are MHC molecules markers of?

"self" | indicate "health" of cells

What are MHC?

group of tightly linked genes important in specific (adaptive) immune responses Present antigens to T lymphocytes Members of immunoglobulin super family

Describe the structure of MHC Class I.

Heavy alpha chain with 3 domains (polymorphic) Light Beta-2 microglobulin chain (same in everyone) Only the alpha chain has a transmembrane region

How does the light polypeptide associate to the heavy polypeptide in MHC Class I?

Non-covalent bonding

What kind of bonds link alpha chains 1 and 2 in MHC class I?

Peptide bonds

What part of MHC Class I is transmembrane?

Alpha chain

Describe the structure of MHC Class II.

2 polypeptides of a similar size, an alpha and a beta chain Both alpha and beta chains have 2 domains Both chains have 1 transmembrane domain

What part of MHC Class II is transmembrane?

Both the alpha and beta chains have transmembrane domains

What is the difference between the types of peptides presented by Class I and Class II?

Class I presents peptides that are smaller than the MHC molecule (8-10 AAs) Class II presents peptides that are longer than the MHC molecule so it often has bits protruding out of the MHC molecule (>13 AAs)

Describe how the structure of MHC allows it to bind to a broad variety of peptides.

It has a binding motif that consists of binding pockets these bind to AA side chains that are relatively conserved Also has an anchor residue which is always 1 AA

What is the name for the Human MHC region in the genome and where is it?

Human Leukocyte Antigen | on Chromosome 6

What are the types of MHC Class I genes for HLA?

A, B, C

What are the types of MHC Class II genes for HLA?

DP, DQ, DR

MHC gene expression

``` MHC is polygenic: several class I and II loci Expression is co-dominant (mat and pat both expressed) ```

Where are MHC class I expressed?

All nucleated cells (at various levels) | Expression may be altered during infection/ by cytokines

Where are MHC class II expressed?

Normally only on "professional" antigen presenting cells May be regulated by cytokines Restricted pattern

Why are human MHC genes described as highly polymorphic and what is the consequence of this?

Large number of alternative different versions of the same gene within the population So people have different immune responsiveness

What is an MHC haplotype?

Group of MHC alleles linked together on a single chromosome

How many MHC haplotypes do we have?

2: 1 maternal 1 paternal

Reality of MHC allele distribution

Not randomly distributed | Some alleles are much rarer/ segregate with race

What is the function of antigen presenting cells (APCs)?

Present processed antigen (peptides) to T lymphocytes to initiate an acquired immune response

Name 3 antigen presenting cells

Dendritic cells (DC) B lymphocytes Macrophages (activated)

Why are there 2 pathways of antigen presentation?

Antigens in different locations require different responses | Different pathways present to different T cell subsets

What are endogenous antigens and what do they present to?

``` Antigen synthesised in cytoplasm of infected cell Present to class I restricted CD8 T cells ```

What are exogenous antigens and what do they present to?

``` Antigen captured from external environment Present to class II restricted CD4 T cells ```

Describe the process of antigen presentation via MHC Class I.

Protein made inside cell- endogenous antigen in cytosol Chopped up to generate peptides Transporter protein (TAP) transports peptides into ER for them to associate with Class I heavy chain and beta-2- microglobulin. Various other proteins help them fold up, once complex of these 3 components are assembled, molecules can go via Golgi to cell surface for possible recognition by CD8 T Cell

Describe antigen presentation via MHC Class II.

``` Antigens are endocytosed Class II Polypeptides (alpha and beta chains) go into ER In ER associate with invariant chain which directs class II molecules into vesicles In these vesicles, proteases chop invariant chain to form CLIP protein CLIP protein is replaced by the antigen. ```