T Cell Development Flashcards
1
Q
Thymus
A
- major but not exclusive site for the maturation of T cells
- site of TCR gene rearrangements
- provides the appropriate microenvironment for the maturation of precursors and their selection (pos and neg) based on their TCR specificities
- site of ordered stages of maturation that have been phenotypically identified and functionally committed
2
Q
Thymus 2
A
- immunodeficiency associated with defects in T cell function caused by- neonatal thymectomy, DiGeorge’s Syndrome, natural mutations
- only about 3% of the thymocytes ever leave the thymus, a site of maturation, cell proliferation, and cell death by apoptosis
- very active in fetal and early life, it later undergoes involution but can be reactivated as a site of thymocyte development in older individual
3
Q
embryonic thymic development
A
- thymus formed from the fusion of 3rd pair of pharyngeal pouch-endoderm-and cleft- ectoderm
- mesenchyme surrounding the epithelial components condense to form the capsule. The mesenchyme also penetrates the thymic rudiment to form the trabeculae
- hematopoietic precursors seed the thymic rudiment beginning at 8 weeks gestation
4
Q
cellular organization of the thymus
A
- cortex and medulla
- capsule and trabeculae
- cortico-medulllary junction
- medulla has hassalls corpuscles
5
Q
immigration and emigration from thymus
A
- T cell precursors (prothymocytes) derived from fetal liver and bone marrow seed the thymus
- thymic anlage produces chemotactic factors that attract T cell progenitors
- cells that seed the thymus enter at the cortico-medullary junction via blood vessels
- thymocytes that survive the rigors of selection leave the thymus from venules in the medullla-also controlled by chemokines and sphingosine 1-phosphate receptors
6
Q
T cell and flow cytometry
A
-T cells go from double neg to double pos to CD4 or CD8 pos
7
Q
Double negative cells
A
- 2-5% of total thymocytes
- contain least mature cells, considerable cell division
- 2/3 are triple neg based on TCR expression
- TCR beta, gamma, delta rearrangement occurs at this stage
- 1/3 are mature TCRdelta/gamma and TCR alpha//beta cells
8
Q
double positive cell
A
80-85% of total thymocytes
- TCRalpha rearrangement here
- most have rearranged TCRalpha and beta genes and express low levels of TCR
- small subset have high levels of TCR (most maturem positively selected cells)
- small subset is actively dividing (earliest DP cells
- most apoptosis occurs here, very sensitive to apoptosis inducing agents, especially glucocorticoids
9
Q
Single positive cells
A
- 10-15% of total thymocytes
- most are mature cells with high levels of CD3 and TCRbeta
- CD4:CD8 approx 2:1
- most SP cells are functionally mature and are destined to leave the thymus
- small subsets of SP are immature (ISP)-have low CD3 and TCRbeta-transitional cells that are on the way from DN to DP
10
Q
Checkpoint 1
A
- assesses whether TCRbeta chain functionally rearranged (like heavy chain on B cell)-need TCRbeta and pTalpha and maybe CD3 on pre-TCR cell, Beta checkpoint slightly beforehand
- consequences of passing checkpoint:
- allelic exclusion at the TCRbeta locus, proliferation, expression of CD4 and 8, no TCRgamma transcription, initiation of alpha rearrangement
- what stim?- no known ligand, preTCR can mediate signal without ectodomains of pTa and TCRb
- inhibited by no RAG, no CD3, no TCRbeta, no pTa
11
Q
Checkpoint 2
A
- cell now has mature TCRalpha and is heading toward single positive
- assesses whether TCRa is functionally rearranged, TCR is self MHC restricted, whether TCR is auto reactive
- consequences of passing: maturation of thymocyte to functionally competent SP cell, establishes a self MHC restricted, non-autoractive TCR repertoire with appropriately matched co-receptors and functional potential
12
Q
how is specificity of abTCR assessed?
A
-requires peptide/MHC molecules interactions to induce a signal
13
Q
if no interaction
A
-dies
14
Q
if interaction too strong
A
-dies
15
Q
ligands for pos/neg selection
A
- ligands are peptide?MHC complexes expressed on stromal and hematopoietic cells. peptides are derived from endogenous sources in the thymus or serum components
- critical to delete thymocytes expressing TCRs that would react with BM-derived APCs in the periphery-need to present self/endogenous peptides to shape repertoire
- Aire TF produces peptides/antigens from other specific locations to check T cells-no aire=autoimmunity
