T cell Diversity Flashcards by HuiXin Chen

What are the two phases in an immune response graph?

Expansion phase followed by contraction phase

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What can T cells TCR be made up of?

Alpha and beta chains
Gamma and delta chains

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What TCR do CD4 & CD8 have?

Alpha-beta chains

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What is an iNKT?

Invariant natural killer T

Expresses an invariant aβ TCR and a number of cell surface molecules in common with natural NK cells

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What are MAIT cells?

Mucosal-associated invariant T cells

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What MHC do MAIT bind to?

MHC Class I restricted

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What initiates TCR arrangement?

Pre-cursor committing to T-cell lineage

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What type of selection do T cell go through?

Positive and negative selection

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What happens when T cell mature?

Leave thymus to go to secondary lymphoid organ where they can encounter antigen

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Before T cell encounter an antigen what are they considered?

Immunologically naive

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How do T cell precursors commit to T cell lineage?

Notch signalling helps determine whether they become CD4+ helper T cells or CD8+ cytotoxic T cells

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How many constant regions are in alpha and beta chains?

V and J segments with 1 constant region
V,D and J segments with 2 constant regions

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What type of dimerization do TCR have?

Heterodimers between alpha and beta chain

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What does RSS stand for?

Recombination signal sequence

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What is the V segment recombination signal sequence?

Heptamer
23 base pair spacer
Nonamer

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What is the J segment recombination signal sequence?

Heptamer
12 base pair spacer
Nonamer

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What would happen without the 12/23 rule when there is a forward and reverse gene present?

V genes can recombine together because one is in the forward direction and the other is in the reverse direction

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What happens when forward-oriented V gene segment recombines with downstream gene segment?

Alignment of the two RSS regions loop out intervening DNA
This loop is excised from chromosome = deleted signal joint
Giving a recombination

What happens when reverse-oriented V gene segment recombines with downstream gene segment?

Alignment of RSS regions forms the intervening DNA into coiled configuration
Coiled region is retained in the chromosome
Inverted orientation of recombination???

What happens when 12/23 rule is present?

RAG1/2 recognize the 12/23 recombinatorial signal sequence
Synapsis of two RSSs = covalently closing DNA hairpin

What creates junctional diversity?

TdT adds random nucleotide

What is the mechanism of generating junctional diversity?

RSS brought together
RAG complex generates DNA hairpin at coding ends
Artemis: DNA-PK complex opens DNA hairpins = generating palindromic P-nts
Tdt adds random nucleotides
Pairing of strands
Unpaired nucleotides = removed by exonuclease
Gaps are filled by DNA synthesis and ligation = form coding joint

What is the role of sequential TCR rearrangement?

Repeated rearrangements can rescue non-productive VJ alpha joins

What does CDR3 of both alpha and beta chain recognize?

Antigen-peptide recognition

What do CDR1/2 of alpha chain recognize?

N terminus of MHC

What do CDR1/2 of beta chain recognize?

C terminus of MHC

Describe CDR1/2 genes

V-encoded and germline encoded

Describe CDR3 genes

J-encoded in alpha D-J encoded in beta Both = hypervariable because of nucleotide additions via TdT

Difference in TCR gamma-delta recombination?

A lot less diverse Delta chain genes sit in alpha chain

If there is too much diversity of TCR, what are the potential issues?

TCR do not recognize (self) MHC TCR do not recognize self antigens

What happens in the medulla region of thymus?

Thymocytes mature and cellular degradation occurs

What happens in the cortex region of thymus?

Immature thymocytes start there = bone marrow origin

When is the thymus fully developed in humans?

At birth

What is thymic involution?

When thymus begins to shrink after puberty?

When is T cell production highest?

Greatest before puberty

Order of T cell development

Hematopoietic stem cells Common lymphoid progenitor (CLP) PreT cell = thymus CD4+ or CD8+ = peipheral blood

What happens in the first step of thymocyte maturation?

CLP enters thymus and receives signals from Notch1 receptor Notch1R causes upregulation of TFs = TCF1 and GATA3 These TF commit CLP to the T cell lineage CLP develops and upregulates the gene RAG1

What happens in DN2 of thymocyte maturation?

RAG1 gene recognizes 12/23 rule and cleaves Recombination happens in the beta locus Once beta chain is recombined = can be successful or non-productive

What happens in DN3 of thymocyte maturation?

If recombination is non-productive ou will not get pairing with pTa = no pre-TCR made If successul = can pair with pTa so you can form pre-TCR

What is the point of the pre-T cell alpha?

Checkpoint to see if there is successful beta chain recombination

When is RAG1 downregulated?

Only when there is a positive pre-TCR signal This is because recombination is no longer needed

What happens when there is a good pre-TCR alpha?

RAG1 will be downregulated Cell will receive signal and start to proliferate

What is the DN4 part of thymocyte maturation?

After proliferation RAG1/2 is expressed again This causes alpha chain rearrangement