Lecture 9 Flashcards
Where is thymus located?
On top of heart
What can HSCs become in thymus?
CD4
CD8
NKT
Tregs
When is thymus colonized by HSCs?
7th week of gestation
When does thymus begin to produce T cells?
12-13th week of gestation
What is DiGeorge syndrome?
- Deletion of chromosome 22
- Present at birth: congenital
- Recurrent infection due to absence of thymus and T cells
- Thymus transplant fixes T cell deficiency
Where is FoxN1 located?
Chromosome 17
What does FoxN1 code for?
TF essential for maturation of thymic epithelial cell progenitors
What does FoxN1 mucation cause?
- Failure of thymus to develop
- Showed thymic epithelial cells were required for normal thymus which was required forT cell development
How can FoxN1 be treated?
Thymic implant
What is found in thymic cortex?
Developing T cells
What is found in thymic medulla?
Mature T cells
What is found in thymic septa?
Firbroblasts
What are TECs?
Thymic epithelial cells
Function of TECs??
- Cytokines required for growth/differentiatoin of T cells
- Notch cells required for T cell commitmen
- Expression of MHC for selecting T celsl
3 types of TECS
Cortical
Medullary
Hassals
What do TECs derive from?
Endoderm
Where do APCs cluster in thymus?
Cortical medullary junction
Functions of APC in thymus?
Present antigen for Differentation
Destruction of self reactive T cells
What are thymocytes derived from?
Bone marrow HSCs
Tool for distinguishing T cell types?
Flow cytometry
Good source of HSC CD34 blood cells for transplant ?
Umbilical cord blood
What happens to HSC when it enters thymus?
Lineage potential restricted to T cells
Why does immune system decline in elderly?
T cell production slows
4 developmental steps in T cells?
- T lineage commitment
- Proliferentiation and differentiation
- Pos/neg selection
- Maturation
What does notch signalling do?
- Causes CD34 cell to move away from myeloid lineage (B, moncyte, DC) where then can now only become T/NK
- Further notch signaling terminates potential of NK develoment
Where does notch signal come from?
Notch ligand DL4 & 1
What is the Pre T cell?
- Commited to T lineage
- Expresses CD1A
- Rearranging Gamma, delta, and beta gens
What can pre T cells become?
Alpha Beta T cell
Gamma Delta T cell
What is necessary for recomination of pre T?
RAG1/2
IL7
What is IL7 required for?
T cell rearrangment
Stage after pret T?
- CD4ISP - CD4 immature single positive
- Exress CD3/4
- Can become alpha beta or gamma delta
What ends rearrangement?
ERK
What expresses CD3
ISP
What is beta selection?
- Selects only ISP cells with functional TCR beta genes
- Rest will be signalled to die
What cells undergo beta selection?
ISP
What happens to ISP cells selected for survival in beta selection?
- Become double positive cells
- Express both CD3 and CD4
T cell selction generate allelic exclusion?
- No
- Positive seletion will ensure that each cell has only one specificity however
What do DP cells rearrange?
Alpha chain
What does alpha chain rearrangment cause?
Delta deletion
Can DP cell have two different alpha chains?
Yes but positive selction will fix this
What can DP cell become?
CD4 or CD8
What happens in positive selection?
- DP cells presented with self antigen in MHCI/II and if they have low affinity they surive
- Surviving cells shut down RAG and replicate
What happens to DP cells that do not recognize self peptide?
Undergo apaptosis
What does positive selection skew towards
Reaction to self peptide and autoreactive T cells
What is negative selection?
Deletion of T cell with strong affinity to MHC and antigen
What does negative selection establish?
Central tollerance
Where does negative selection occur?
Cortical medullary region where [DC] is high to eat self reactive cell
What is AIRE?
Gene that allows for expression of peripheral tissue antigen in thymic cells to test for self reactivity
Diseases with AIRE deficiency?
APECED / APS1
What are APECED / APS1?
Auto immune deficiency resulting from AIRE deficiency
What to TCR gamma delta cells develop from?
ISP
Gamma delta T cell CD4 or 8 positive?
Negative for both
Gamma delta T cell CD4 use MHCI or MHCII?
Neither - bind antigen directly
What do NKT cells develop from ?
DP T cell
Function of NKT?
Rapidly produce cytokines necessary for TH1 & TH2 when triggered
What do Tregs develop form?
CD3/4 positive T cells
What is required for Treg development?
FOXP3
T reg disease?
IPEX
