T Cell Development

Question 1

Immunosenescence

Answer 1

T cell pool remains stable until old age (long life-span and self-renewal) but slowly loses function

Question 2

DiGeorge syndrome

Answer 2

Lack of thymus leads to a T cell deficiency

Question 3

Purpose of stromal cells in the thymus

Answer 3

Provide signals for growth and survival

IL-7, Flt3L, Notch-1

Question 4

Development if T cells in the bone marrow

Answer 4

Only goes as far as CLP-Flt3-hi before migrating to the thymus

Question 5

What molecules are upregulated by T cells whilst as CLP in the BM

Answer 5

L-selectin, CCR7, CCR9

Question 6

Flt3

Answer 6

Cytokine receptor involved in regulating the survival, proliferation, and differentiation of hematopoietic stem cells and progenitors by responding to its ligand (FLT3L)

Question 7

Early thymic precursors

Answer 7

First T cells to seed in the thymus as double negatives

Question 8

Basic sequence of T cell developmental stages

Answer 8

Common Lymphoid Progenitor (CLP)

Early Thymic Precursor (ETP)
(also Double Negative (DN))

Double Positive (DP)

Single Positive (SP)

Question 9

Localisation of DN1

Answer 9

Move from corticomedullary junction towards the outer cortex to interact with stromal epithelial cells

Question 10

Signalling on DN1s

Answer 10

IL-7; survival and proliferation
Notch-1; T cell commitment

Question 11

Process of Notch-1 signalling

Answer 11

Extracellular domain binds Notch ligand
The intracellular domain is cleaved off and migrates to the nucleus
Acts as a coactivator for transcription

Question 12

Localisation of DN2s

Answer 12

Cortex

Question 13

Function within DN2s

Answer 13

Simultaneous rearrangement of TCRβγδ

Question 14

Localisation of DN3s

Answer 14

Sub-capsular region

Question 15

Function within DN3s

Answer 15

PreTCR expression and β-chain selection (preTCR checkpoint)

Question 16

DN4 localisation

Answer 16

Moving back towards the cortex

Question 17

Function within DN4s

Answer 17

Proliferation, allelic exclusion of the β-chain and rearrangment of the α-chain

TCR checkpoint

Question 18

Difference between TCRβ, γ, δ rearrangements

Answer 18

Occur simultaneously but αβ Τ cells only need a productive TCRβ rearrangement whilst γδ requires successful γ and δ chains

Question 19

Why do αβ Τ cells need only a productive β chain

Answer 19

β chain associates with preT and CD3 complex which induces β selection, commitment, and proliferation

Question 20

3 reasons why αβ T cells are favoured

Answer 20

Lots of Vα and Vβ segments with two DJC regions means more attempts

Proliferation of large pool for trying out α rearrangements

Deletion of the δ-chain within the α-chain

Question 21

When are γδ T cells regulated

Answer 21

During early development
Come out of the thymus in early waves before birth, likely regulated by transcription factors and gene segment accessibility within chromatin

Question 22

Structure of γδ T cells when exiting the thymus

Answer 22

Mature and do not receive further education

Question 23

Localisation of DP T cells

Answer 23

Migrate from the subscapular region deeper into the cortex

Question 24

Structure of DPs

Answer 24

Have undergone α-chain rearrangement and start to express mature, αβTCR.
Upregulate both CD4 and CD8

Question 25

cTECs

Answer 25

Cortical thymic epithelial cells

Question 26

Positive selection of DP t cells

Answer 26

Interactions with cTECs and macrophages, MHC restriction. Only ~2% survive.

Question 27

Why do DP cells express both CD4 and CD8

Answer 27

To ensure they can interact with either MHC II or MHC I and differential signalling will commit to either CD4 or CD8 SP thymocytes

Question 28

Negative selection during T cell development

Answer 28

Eliminates autoreactive thymocytes binding to MHC/peptides Creates central tolerance via apoptosis and clearance via macrophages. Can take place in either the thymic cortex or medulla as DP or SPs respectively

Question 29

mTECs

Answer 29

Medullary thymic epithelial cells

Question 30

What do mTECs express

Answer 30

AIRE

Question 31

AIRE

Answer 31

Autoimmune regulator expressed by mTECs during T cell development. Binds to histones with closed chromatin and recruits transcription factors and RNA polymerases for expression of MHC and proteins found outside the epithelium to test during negative selection

Question 32

Selection paradox in T cell development

Answer 32

Both positive and negative selection, must recognise self-MHC but not be too autoreactive

Question 33

Affinity model of selection during T cell development

Answer 33

Fate determined by binding/signal strength No signal - death by neglect Low signal - positive selection High signal - negative selection

Question 34

Altered peptide model of selection during T cell development

Answer 34

cTEC processes different peptides for positive selection Unique catalytic subunit in the thymic proteosome results in an altered low affinity peptide

Question 35

Signal that commits to CD4

Answer 35

Th-POK

Question 36

Signal that commits to CD8

Answer 36

RUNX3

Question 37

Instructive model of CD4/8 T cell commitment

Answer 37

MHC restriction signals directly for cell fate CD4/MHCII engagement -> CD4 program CD8/MHCI engagement -> CD8 program

Question 38

Stochastic model of CD4/8 T cell commitment

Answer 38

Positively selected cells are randomly selected for either CD4 or CD8 and then they only survive if the TCR signal is maintained

Question 39

Kinetic signalling model of CD4/8 in T cell commitment

Answer 39

Positively selected cells transiently downregulate CD8 and commit to CD4 if they recieve a continuous signal, or commit to CD8 if the signal is interrupted.

Question 40

Thymic exit process

Answer 40

Mature CD4/CD8 SP T cells migrate back to the corticomedullary junction using CCR7 They exit the thymus into the blood following S1P and then circulate to secondary lymphoid tissues

Question 41

NKT cells restricted TCR usage

Answer 41

Vα24Jα18 paired with Vβ11

Question 42

Selection of NKT cells uses ____ instead of MHCI/II

Answer 42

CD1d on other DP cells

Question 43

SIgnals that contribute to NKT and MAIT cell selection

Answer 43

SLAM

Question 44

Transcription factor of PLZF

Answer 44

Drives the development of NKT cells and MAIT cells

Question 45

What antigens do NKT cells recognise

Answer 45

Lipids and glycolipids This includes both self lipids that have been upregulated in response to stress and foreign glycolipids from pathogens.

Question 46

MAIT cells

Answer 46

Mucusal-associated invariant T cells that develop from DP thymocytes

Question 47

Restricted TCR usage of MAIT cells

Answer 47

Vα7.2Jα33

Question 48

What is the MHC used by MAIT cells

Answer 48

MHC-related protein 1 (MR1) on other DP thymocytes

Question 49

What antigens do MAIT cells recognise

Answer 49

Vitamin B (riboflavin)-related antigens produced by yeast and bateria loaded onto the MR1. MAIT cells do not develop in germ free mice

Question 50

MR1 expression

Answer 50

Not expressed in the absence of an antigen

Question 51

Rolling of circulating naive T cells enter the LN via HEVs

Answer 51

L-selectin / PNAd

Question 52

Activation of circulating naive T cells enter the LN via HEVs

Answer 52

CCR7 / CCL21

Question 53

Arrest of circulating naive T cells enter the LN via HEVs

Answer 53

LFA-1 / ICAM-1

Question 54

What does a naive T cell do in the LN

Answer 54

Scans for Ags; - if none, exit following S1P out the efferent lymphatics - Ag, activation retained by CD69 upregulation, proliferation/differentiation

Question 55

Memory T cell pools overview

Answer 55

Retain long term memory for recall responses Stem cell and central memory T cells (Tcm) recirculate through the LNs.

Question 56

Effectory memory T cells overview

Answer 56

Tem, alter adhesion molecules and are targeted for certain tissues - CD4 become different T helpers depending on type of pathogen, cytokine environment, innate responses, and types of APCs - CD8 differentiates into cytotoxic effectors

Question 57

Barrier to activation of CD8 T cells

Answer 57

HIgher and requires strong antigens and CD4 T cell help (IL-2) (memory CD8 T cells need less costimulation)

Question 58

What molecules are upregulated by CD8 T cells

Answer 58

Cytotoxic molecules such as perforin/granulysin, granzyme

Question 59

Mechanism of granzymes

Answer 59

Apoptosis via Bid-induced release of mitochondrial cytochrome-c and caspase activation

Question 60

How many cells can a CTL kill

Answer 60

16 target cells in succession