T Cell Development Lecture 8 Flashcards
By the time the baby is born is the peripheral T cell repertoire established?
Yes
Is the functional maturation of thymic epithelial cells required for the development of normal thymic architecture and normal development of T cell subtypes and initial establishment of tcell pool?
yes
What are two forms of evidence that the thymus is responsible for thymopoiesis?
- DiGeorge syndrome–>No thymus and T-cells not detectable–>thyrus implants gives rise to T cell number and restores immune response
- FOXN1-mutation in FOXN1 No hair, no thymus
What cells is the thymus responsible for develop?
- CD4 T helper
- CD8 T cytotoxic
- regulator T cells (Tregs)
- natural killer T cells
When do mature T cells egress the thymus?
13-14 th week
What do you find in the capsule of the thymus?
fibroblasts
What is in the cortex?
Developing T cells
What is in the medulla?
Fewer mature T cells
What happens in the corticomedullary junction?
Where HSC and T cells come and leave the thymus-where blood vessels are
What is the hassal body?
mature epithelial cell
The thymic stroma is made of two types of cells, what parts of the thymus do these two types of cells make up?
Fibroblasts: capsule, septa with blood vessels
Epithelial cells: cortical, medullary and hassall’s body
What are the 3 types of cellular composition in the thymus?
thymic stroma
macrophages and dendritic cells
lymphoid compartment
What are all thymic epithelial cells derived from?
Endoderm
What is the cell surface ligand on thymic epithelial cells?
Delta like 1,4
-ligand for the notch receptor
Do thymic endothelial cells express major histocompatiblity comple, and express peripheral tissue antigens?
Yes
MHC 1 and 2
Yes
Where are macrophages and dentritic cells concentrated in the medulla?
Cortico-medullary junction
What do the macrophages in the thymus do?
Deletion of autoreactive T cells, macrophages will kill these through negative selection
What is the most immature t cell?
double negative
Are there more CD4 pos or CD 8 pos?
CD 4
What happens to your thymus when you get older? What does this mean for your t-cell production?
Thymus gets fatty
older you get the less t-cells you make
What type of HSCs go to the thymus?
CD34+
Do few mature T cells ever go back to the bone marrow or thymus?
yes
What are the 4 developmental steps that occur in the maturation of T cells
T lineage commitment: restricted of lineage choices
Proliferation: expansion of commited cells
Differentiation: gaining of new surface markers
Maturation: selection and gaining of immune functions
What induces T lineage commitment and terminates lineage plasticity?
Delta like 1 or 4 ligand on TEC with notch receptor on HSC
What is the first step of the Pre T cell?
TCR B gene rearrangement
using RAG 1 and RAG2 and IL7R gamma
(without IL7Rgamma–>SCID)
What is expressed with the rearranged beta chain on the PreTCR complex?
Surrogate alpha chain
rearranged betta chain
CD3
After TCR B gene rearrangement what occurs to select for the functionally rearranged TCR beta?
Beta Selection
What happens during beta selection?
- Allelic occlusion–>degrading RAG proteins
- rapid proliferation
- increased expression of CD3 complex
What does signaling through the pre-TCR induce and what does this create a bias for?
- induces significant proliferation of ISP cells
- bias the ISP toward TCR alpha beta lineage over gamma delta
What happens to ISP cells after beta selection what type of cells do they develop into?
- express CD8
- develop into CD8 CD4 DP cells
What happens after the cell becomes a DP cell?
RAG expression is re-expressed and alpha genes are rearranged
-caused deletion of delta locus
Is there allelic exclusion with with alpha rearrangement?
No
- it is possible that there are two different rearranged alpha chains associated with a common beta
- positive t cell section will ensure each T cell only has one functional specificity-although tow different alpha chains are expressed
How many chains does the signaling component have?
5 different chains
What type of selection do the DP alpha and beta rearranged cells go through? What does this coordiante?
Positive Selection
- must see both antigen and MHC on cortical epithelial cells to survive to survive
- coordinates either CD4 pos or CD 8 pos
What is bare lymphocyte syndrome?
defect in MHC 2 expression-the development of CD4 pos T cells is affected
TCRs are selected on the basis of self MHC, what does this have the potential to generate?
Autoreactive T cells that may affect autoimmune disease
What does negative selection do?
mechanism for estabilishing central tolerance
What if happens if the signal is too strong?
Kill them
What 2 types of cells induce negative selection? where
- Dendrites and macrophages
- Epithelial cells
- corticomedullary junction
What do mTEC cells do in negative selection, what induces this expression?
express organ specific antigens that mirror peripheral self antigens
expression of these genes are induced by the transcription factor AIRE
What happens in a AIRE mutation? APECED
declined immune response fungal will form
- oral candidiasis
- candidal onychomycosis
- vitiligo with halo naevi-kill malanocytes
TCR gamma delta tcells are derrived from what cells and are they DP or DN and what do they bind to?
- Derived from: ISP cells
- DN
- Bind self lipid antigens
What are the two major types of gamma delta t cells?
mucosal tissue associated with epithelial tissue and circulatory
What are two functions of gamma delta cells?
- kill stressed epithelial cells
2. anti-microbial immunosurveillance (leprae, Tuburculosis)
WHat type of cytokines do gamma delta cells use?
INF gamma which acts on NK and NKT and Th1 cells
What are the cell makers for NKT cells?
Cd56 (NK) and CD3 (Tcell)
What do cells that develop into NKT cells recognize during development?
CD1d/glycolipids on cortical thymocytes
Are NKT cells CD4 pos? CD 8 Pos?
CD4 pos or DN
What 4 places do NKT cells populate?
-liver, spleen, BM, lymph nodes
.2% in peripheral T cell pool
What type of cell markers do Tregs have? What od they do?
CD4 pos and cd25 pos
- have suppressor activity agians autoreactive tcells that may have escaped the negative selction process
- establish dominat tolerance
What type of cell markers do Tregs have? What od they do?
CD4 pos and cd25 pos
- have suppressor activity agians autoreactive tcells that may have escaped the negative selction process
- establish dominat tolerance
What does the development of Treg require?
Thymic stroma lymphopoietin TSLP of hassll’s bodies
What TF is necessary for TREg?
FOXP3
What is an increased level of Treg associated with?
cancer
How are periphery Tregs developed?
- TGF beta induces Treg from CD4 pos cells
- T regulatory type 1: IL10
- T helper 3: oral tolerance induction
What diesase is associated with with mutation of FOXP3 gene?
Immune dysregulation polyendocrinopathy and x linked inheritance
(IPEX)
