Flashcards in Lecture8 - HD T-Cell Maturation & Differentiation Deck (47)
The epithelial component of the thymus derives bilaterally from epithelium of the ______ at _____ week of gestation
The thymic glands are colonized by hematopoietic stem cells at __ weeks of gestation.
What happens with the thymus between 4-7 weeks of gestation?
The thymus begins producing T cells when?
1. 3rd pharyngeal pouch, 4th
3. the primordial thymic glands lose connections with the pharynx and migrate to the final position in the mediastinum forming a single bilobate gland.
4. 12-13 weeks of gestation
Mature T cells egress the thymus and colonize peripheral lymphoid organs when?
Chronicle the development of the thymus from week 3 to week 14 of gestation:
1. 13-14 weeks of gestation
3: epithelia of thymus derives from 3rd pharyngeal pouch
4-7: primordial thymic glands lose connection with pharynx and migrate to mediastinum and form a single bilobate gland
7-8: glands colonized by hematopoietic stem cells
12-13: thymus begins producing T cells
13-14: mature T cells egress the thymus and colonize peripheral lymphoid organs
Why doesn't thymectomy cause immediate immune deficiency if done after a baby is born?
DiGeorge syndrome is caused by:_____
The symptoms of DiGeorge syndrome include:
What is the most significant problem of DiGeorge syndrome that causes most other symptoms?
1. Because by then the peripheral T cell repertoire is established.
2. a large deletion 22q11 locus
3. heart defects, hypoparathyroidism, athymia, recurrent infection, facial features, absence of thymus and T cells
4. absence of thymus and T cell deficiency
How can patients with DiGeorge syndrome be rescued?
transplantation of an allogeneic thymus graft to alleviate T cell deficiency
Allogenic = denoting, relating to, or involving tissues or cells that are genetically dissimilar and hence immunologically incompatible, although from individuals of the same species. = FROM ANOTHER PERSON
The FOXN1 gene is on chromosome __ and encodes:
What happens in a patient with FOXN1 gene mutation?
17, a transcription factor need for functional maturation of thymic epithelial cell progenitors
2. CGA to TGA means no hair and no thymus.
Thymus gland fails to form in utero because the epithelial progenitor cells don't undergo functional differentiation and instead form cyst-like structure. They also fail to recruit hematopoietic stem cells.
How can immune response be restored in patients with FOXN1 mutations?
What does the FOXN1 mutation tell us about how the thymus develops?
1. thymic implant
2. It tells us that maturation of thymic epithelial cells is required for normal architecture development, which is needed for production of T cell subsets and establishing the peripheral T cell pool.
What part of the thymus includes the thymic epithelial cells and fibroblasts?
Where are fibroblasts found in the the thymus?
What critical functions do thymic EPITHELIAL cells provide for T cell development? (4)
1. Thymic stroma
2. thymic capsule and septa
Produce cytokines like IL1,6,7, SCF, and TSLP
express cell surface molecules like ligand Delta-like-1 for the notch receptor
Expression of MHC I or II controls selection of maturing T cells.
- expression of peripheral tissue antigens: ex --> insulin
What are the 3 types of TEC named based on anatomical location?
cortical, medullary, Hassall's
All TEC are derived from:
What allows us to visualize the thymic cells from the cortex and from the medulla?
Keratin 8 for cortex
and Keratin 5 for medulla
Macrophages and dendritic cells mature in the ______ and migrate to the ______
bone marrow, thymus.
Where are macrophages and dendritic cells in the thymus?
scattered in cortex and medulla. high in cortico-medullary junction.
What functions do macrophages and dendritic cells have in the thymus?
1. antigen presentation
2. deletion of autoreactive T cells (NEGATIVE SELECTION)
3. phagocytosis of apoptotic thymocytes
What are the predominant lymphoid cells in the thymus?
In postnatal animals, thymocytes derive from:
What 4 different T cells is the thymus responsible for developing?
State the percentage for the following in thymocytes:
1. Double Positive
2. mature CD4+ T cells
3. immature CD8+ T cells?
4. immature double negative cells
CD4 T helper
CD8 T cytotoxic
The production of T cells increases/decreases with age?
In what age range is daily thymic output the highest?
What is the unique cell surface marker of progenitor cells in the thymus?
When is the migration of CD34pos cells initiated?
1. 2-10 years old
3.7-8 weeks of gestation
Why do the elderly have a less effective immune response?
T cell production decreases with age
Why is cord blood a good source for HSC CD34pos cells for transplant?
What happens to the lineage potential of CD34pos cells when they enter the thymus?
1. Because the migration of CD34pos cells is initiated at 7-8 weeks of gestation and is highly active in the neonatal period.
2. restricted to only T lineage.
What are the 4 key developmental events in generation of mature T cells?
1. T lineage committment
- Restricted of lineage choices
- Expansion of committed cells
- Gaining of new surface markers
- gaining of immune functions
What is the significance of signalling through the notch receptor?
terminates potential to commit to lineages other than T or NK cells
What happens to cells following a Notch signal?
What happens to cells after they become pre-T cells?
cells commit to T lineage, express CD1A and begin to rearrange TCRy,d and B genes. They become pre-T cells***
2. They express CD4 and become CD4ISP.
preTa is expressed, which induces CD3 and forms the preTCR complex with TCRB.
What happens in the B selection process?
What happens to CD3 expression during B selection? up-regulated.
B selection selects cells with productive and functional rearranged TCRB genes
- signaling via the preTCR.
-Cells that don't have a good preTCR die via apoptosis.
-Cells that survive proliferate and expand, generating a lot of thymocytes with TCRaB in the thymus.
What happens to ISP cells that survive B selection?
progress to express CD8 and become double positive cells.
They then rearrange TCRa genes and the d locus is deleted.
What is the last step in T cell development following DP cell formation?
DP cells down modulate one of the co-receptors and mature into either single CD4 or CD8 cells.
Summarize the entire T cell development process starting from Notch signaling.
1. CD34pos cell sends through Notch signal
2. CD34pos, CD7pos, CD1Aneg
3. pre-T cell. committed to T lineage. CD1Apos, CD34lo/neg
rearrangement of y, d, B
4. ISP cell. CD34neg, CD1Apos, CD4pos, CD3lo. expression of preTa. B selection
5. Rearrangement of TCRa. DP cell
6. Becomes either CD4 or CD8. either way will have CD3pos and TCRaBpos
What does positive selection of TCRaB T cells mean?
The interaction of TCRaB/CD3 complex with self peptides and MHC antigens is of high or low affinity?
Why is this?
1. Selection of T cells that recognize antigens presented by MHC molecules
2. LOW affinity
- otherwise the TCR could bind the MHC molecule without the antigen
low; DP cells with low affinity TCR are rescued from apoptosis and proliferate.
What is RAG? What happens to it in positive selection?
How does positive selection skew the TCRaB repertoire?
1 RAG stands for recombination-activating gene.
2.Expression of it is shut down so that further rearrangement cannot happen.
3. skews it toward self peptides and the potential of generating autoreactive T cell clones.
How do bone marrow transplants tell us that developing donor T cells occur on TEC of the recipient?
What happens in negative selection?
Patients who receive bone marrow transplant generate T cells that recognize foreign
antigens in the context of their own MHC antigens and not donor MHC
2. Deletion of mature T cells that bind strongly to MHC/antigens (autoreative T cells)
-negative selection results in the generation of central tolerance