T cell biochemistry

Question 1

the immune system cells all start life where

Answer 1

life in the bone marrow, receiving signals from stromal cells

Question 2

describe T cells

Answer 2

Mature in the Thymus

Regulatory and Cytotoxic

Can further differentiate depending on specific signals

Question 3

describe B cells

Answer 3

Mature in the Bone Marrow

Produce antibodies

Question 4

describe NK (natural killer) cells

Answer 4

Mature in the Bone Marrow, but also secondary lymphoid tissues

Cytotoxic

Question 5

describe antibodies

Answer 5

Antibodies illicit a strong immune response, coordinating many cells of the immune system, and B-cells can develop an immune memory to help in times of further infection.

Question 6

name some things antibodies cannot be used to combat effectively.

Answer 6

Intracellular pathogens

• Bacteria and Viruses
• Tumours

Question 7

what does the immune system need to work efficiently

Answer 7

T cells

Question 8

explain the T cell receptor

Answer 8

Approximately 105 T-Cell receptors on the surface of the T-cell

Consists of 2 polypeptide chains:
- Majority - ⍺β T-cells
- Minority - 𝛾δ T-cells

Each chain has 2 domains, V (Variable) and C (Constant), which are linked by a disulphide bond

Hydrophobic transmembrane domain and a very shot cytoplasmic tail

Question 9

describe some differences between TCR and fab

Answer 9

Antibodies:

Broad sheets of anti-parallel β-sheets

• Hydrophobic side chains are tightly packed between the sheets and held together with disulphide bridges
• Alpha helix is towards the back of T cell receptor

C⍺:

Half of the domain, that closest to the β chain, forms a β-sheet

The other half is made up of loosely packed strand and a short stretch of ⍺-helix
- Held to the one of the strands of the β-domain to this helix

Additionally, the interactions between C⍺ and Cβ is assisted by carbohydrates
- Carbohydrate on C⍺ forming hydrogen bonds with the amino acids of Cβ.

CDR loops:

Fairly similar between an antibody and the TCR, some displacement

V⍺ CDR2
- At a right angle compared to the equivalent loop in the equivalent loop in an antibody.

TCRs have a 4th hypervariable region away from the antibody binding site

Question 10

explain the T-cell receptor gene rearrangement on TCR⍺

Answer 10

similar to the Immunoglobulin light chain

V and J segments

Question 11

explain the T-cell receptor gene rearrangement on TCRβ

Answer 11

similar to the immunoglobulin heavy chain

V, D, and J segments

Question 12

when do genes in T cells rearrange

Answer 12

during T-cell development in the thymus in a process similar to the Germinal Centre Reaction for B-cells

Question 13

do T cell receptors bind antigens directly

Answer 13

no

Question 14

antibodies bind what in the circulation
and make contact with what

Answer 14

bind antigen in the circulation, whether that be free flowing or on the surface of the pathogen

Make contact with discontinuous amino acids only brought together when the antigen is in its tertiary structure

Question 15

what do T cells bind to

Answer 15

to an antigen-protein complex

Question 16

what is an antigen-protein complex

Answer 16

Short, continuous amino acid sequences from an unfolded protein

Presented as part of a protein complex on the surface of an antigen presenting cell

Question 17

what does MHC stand for

Answer 17

Major Histocompatibility Complex

Question 18

how are MHC 1 and MHC 2 similar and different

Answer 18

Closely related in overall structure and function, but differ in their protein subunits

• 2 paired domains nearest the membrane resemble an immunoglobulin
• 2 domains furthest from the membrane produce a peptide-binding cleft

Question 19

explain MHC 1 structure

Answer 19

2 Polypeptide chains

• The ⍺-chain, which makes up 3 domains of the protein and crosses the membrane and forms the entire peptide binding cleft
• Β2-microglobulin associates with the ⍺3 domain

Question 20

explain MHC 2 structure

Answer 20

2 polypeptide chains

• Both the ⍺ and the β chain cross the membrane
• The peptide binding cleft is made up of both the ⍺ and the β chain

Question 21

In order to stimulate T-cells, MHCs need to be what

Answer 21

able to bind a large variety of peptides

Unlike other peptide-binding receptors such as GPCRs
MHC proteins are unstable when not bound to a peptide
- MHC-I binds peptides 8-10 amino acids in length
- MHC-II can bind peptides of any length

Question 22

MHC-I binds and presents what

Answer 22

intracellular peptides that reside in the cytosol

Question 23

Some pathogenic bacteria, and some protozoa, reside inside vacuoles once inside the cell and peptides are presented on what

Answer 23

MHC 2

Question 24

Extracellular pathogens are phagocytosed, and peptides are presented on what

Answer 24

MHC 2

Question 25

describe cross presentation

Answer 25

Some pathogens will not infect phagocytic antigen presenting cells (such as dendritic cells), for example the epithelium Thus, the antigen presenting cell will express MHC-I presenting peptide antigens from the infected cell

Question 26

name some T cell co receptors

Answer 26

CD4 + CD8+

Question 27

describe the T cell co receptor CD4+

Answer 27

T-helper cells Recognises MHC-II

Question 28

describe the T cell co receptor CD8+

Answer 28

Cytotoxic T-cells Recognises MHC - 1

Question 29

describe T cell co receptors

Answer 29

TCR binds directly to the MHC peptide binding cleft CD4 and CD8 bind to an invariant site away from the peptide binding cleft

Question 30

The TCR⍺β heterodimer, along with either CD4 or CD8 is not sufficient to initiate what

Answer 30

activation of the T cell

Question 31

what 2 things are needed for TCR signal transduction

Answer 31

CD3 complex ζ-chain – zeta

Question 32

what is CD3 complex made up of

Answer 32

CD3𝛾 CD3δ - delta CD3ε - epsilon

Question 33

TCR signal transductions signalling is initiated by what

Answer 33

initiated by ITAMs in the 𝛾, δ, ε, and ζ chains - Immunoreceptor Tyrosine-based Activation Motifs - CD3𝛾, δ, and ε all have 1 ITAM - ζ chain has 3

Question 34

in TCR signal transduction, Each ITAM has 2 Tyrosine residues what happens to these

Answer 34

Become phosphorylated by tyrosine kinase Lck, which is colocalised with the CD4/CD8 coreceptor, when the receptor binds its ligand (MHC + peptide) Phosphorylation leads to the recruitment of Zap70

Question 35

what next happens in TCR signal transduction, to Zap70

Answer 35

phosphorylates LAT (Linker for Activated T-cells), which leads to the recruitment of PI 3-kinase

Question 36

in TCR signal transduction, what happens after the recruitment of PI 3-kinase

Answer 36

the T-cell signal branches into distinct modules, leading to the activation of different transcription factors with different effects

Question 37

during TCR signal transduction different transcription factors with different affects are activated, name these and describe them

Answer 37

NFκB – the master inflammatory transcription factor AP-1 – differentiation, proliferation, and apoptosis NFAT - Requires Calcium influx - Family of 5 proteins differentially expressed in different tissues - For T-cells, NFAT is important for activation and the production of specific signalling molecules

Question 38

Derived from the bone marrow, but all the development happens where

Answer 38

in the thymus

Question 39

what happens in T cell maturation

Answer 39

Similar to B-cell maturation: - Gene re-arrangement - Testing of the new receptor - Release of the new T-cell or - cell death Round of positive and negative selection - Dependent on Notch signalling

Question 40

CD4+ T-cell produces different subtypes depending on what

Answer 40

the signal

Question 41

what are the subtypes CD4+ T-cell produces

Answer 41

Tfh – B-cell formation Th1 - type 1 response. intracellular bacteria, protozoa, and viruses. autoimmunity Th2- type 2 response. extracellular helminths and venoms. allergy and asthma Th17 - type 3 response. extracellular bacteria and fungi. autoimmunity Treg- immune tolerance. immune regulation CD4 CTL? - MHC2-dependent. killing

Question 42

what are CD8+ subsets

Answer 42

cytotic lymphocytes - MHC 1 dependent - killing

Question 43

explain CD8 Cytotoxic T-cells

Answer 43

Kill cells by inducing cell death by either intrinsic or extrinsic pathways of apoptosis: - Extrinsic – binding of Death Receptors - Intrinsic – Mitochondrial degradation Both require Caspase enzymes: - Proteases - Initiator Caspases Promote apoptosis by cleaving and activating other caspases Intrinsic = Caspase 9 Extrinsic = Caspase 8 and 10 Effector Caspases - Initiate the cellular changes associated with apoptosis - Both pathways use Caspase 3, 6, and 7