Lecture 11 - Defects in T Cell Development Flashcards
describe the development of the thymus and its stroma (3 stages)
and the TFs involved in each step
- thymus organogenesis - TBX1
- TEC development - FOXN1
- TEC function - AIRE
Describe development of TECs
underdeveloped cells migrate to pericardium from the pharynx and develop into TECs btwn 1st and 2nd trimester in humans
what causes DiGeorge Syndrome?
deletion in long arm of chromosome 22
2 types of DiGeorge Syndrome
- INCOMPLETE
- COMPLETE
3 symptoms of incomplete DiGeorge Syndrome
- variable thymic size
- increased susceptibility to infections
- immunodysregulation leading to autoimmunity
2 symptoms of complete DiGeorge Syndrome
- no thymus
- SCID –> T cell deficiency
why do people have variable symptoms in DiGeorge Syndrome
diff genes are lost
genes lost in DiGeorge Syndrome
diff genes but ALWAYS TBX1
role of TBX1
essential early on for pharyngeal segmentation of the thymus (embryonic day 9 in mouse)
what happens if Tbx1 expression is lost before embryonic day 9?
no thymus –> required to establish thymic tissue
what happens if Tbx1 expression is lost after embryonic day 9?
thymus is normal, therefore gene is dispensible after day 9
2 treatments of DiGeorge Syndrome
- transfer mature T cells
- thymus transplant
describe the transfer of mature T cells for DiGeorge Syndrome
mature T cells from donor are injected into patient but they won’t get full TCR repertoire
describe thymus transfer for DiGeorge Syndrome
not full thymus –> use thymic splices that have been depleted of hematopoietic cells so only epithelial cells remain
what type of immunodeficiency occurs with FOXN1 deficiency?
Nude SCID
what is FOXN1?
TF expressed by epithelial cells in skin and thymus
role of FOXN1 in thymus
necessary for thymic organogenesis –> allows differentiation of cTECs and mTECs from progenitors
what does FOXN1 deficiency cause?
no thymic epithelial cells –> no thymus –> no T cells
treatment for FOXN1 deficiency?
thymus transplant
what does APECED stand for?
Autoimmune PolyEndocrinopathy Candidiasis Ectodermal Dystrophy
another name for APECED?
Autoimmune Polyendocrinopathy Syndrome Type 1 (APS-1)
what causes APECED/APS-1?
Aire deficieny
what does Aire stand for?
autoimmune regulator
do all patients with APECED have the same phenotypes?
No
why do patients with APECED have different phenotypes?
Aire-deficiency can mean there’s full dysfunction or alter levels of certain genes/pathways –> diff tissues are targeted
6 possible symptoms of APECED
- vitiligo
- alopecia
- hypoparathyroidism
- ovarian/testicular failure
- type 1 diabetes (uncommon)
- chronic candida infection
2 types of treatment for APECED
- symptom management
- immunosuppression
what cells become autoreactive in APECED?
T cells and B cells
how do autoreactive B cells contribute to diversity of phenotypes in APECED?
autoreactive B cells make auto-antibodies that target IFN and IL which can block the IFN and IL responses
what is the result of RAG deficiencies?
B and T cell deficiency
what type of mutations give similar phenotypes to RAG deficiency?
mutations in genes involved in recombination of receptor gene segments
2 therapies for RAG deficiency
- hematopoeitic stem cell transplant
- gene correction/gene editing
how does gene correction/editing work?
fix mutations which corrects gene expression in patient’s progenitor cells and re-implant
what type of therapy is NOT effective in RAG deficiency?
thymic transplant
why is thymic transplant not effective for RAG deficiency?
RAG deficiency directly impacts hematopoietic cells, not thymic tissue
3 causes of X-linked SCID
- common gamma chain deficiency
- IL-7Ra deficiency
- JAK3 deficiency
what do common gamma chain, IL7Ra, and JAK3 deficiencies lead to?
impaired cytokine signaling –> T cell deficiency
2 therapies for X-linked SCID
- hematopoeitic stem cell transplant
- gene correction/editing
why can we use hematopoeitic stem cell transplant for X-linked SCID?
because we can give cells with the proper cytokine receptors and signaling molecules so they can make mature T cells
what does thymic atrophy lead to?
loss of thymocytes and/or destruction of thymus –> leads to decreased naive T cells and reduces TCR diversity
what are causes of thymic atrophy?
- aging
- changes in sex hormones
- inflammatin
- infection
- stress
- cytoablative therapies
4 results of age-related thymic atrophy
- decrease in TECs
- loss of definitive cortical-medullary junctions
- increase in perivascular space
- increase in adipose tissue
what is an indirect way to determine thymic function?
look at egress of naive T cells from thymus
describe looking at naive T cells in circulation to determine thymic function
expect to see them going into circulation to meet new Ag throughout lifetime
if there is reduced number of naive T cells in circulation, indicates poor thymic function
what is a more direct way of looking at thymic function?
detecting the amount of TCR excision circle harbouring signal joint (TREC)
What are TRECs?
circular episome produced during recombination of TCRalpha chain
how can we use TRECs to indicate thymic function?
TRECs in T cells normally go away but naive T cells will still have them so we can detect the number of TRECs to indicate the number of naive T cells in circulation
how does the number of thymic emigrants change with age?
reduced thymic output with age
how does the number of thymic emigrants change after thymectomy?
reduces even more with age compared to non-thymectomy patients
but still some naive T cells can egress because thymectomy doesn’t remove the whole thymus
what type of surgery removes the thymus?
heart surgery
how does adult thymectomy affect survival?
significant reduction in survival with thymectomy
what is the main cause of age-related thymic atrophy?
thymic stromal cell degeneration, specifically TECs
describe the number of thymocytes in young vs old mice who have received fetal thymic graft
why is this significant?
old mice maintain thymocytes
therefore, maintaining the structure of the thymic epithelium is necessary for thymocyte
what causes thymic atrophy with age and in pregnancy?
androgens!
what was the early study that showed that androgens induce thymic atrophy?
when various animals were castrated, thymus growth persists and atrophy slows down
what is an external factor that can impact thymic function?
infections
2 ways that infection can induce thymic dysfunction
- pathogen infects thymic cells
- immune response produces inflammatory cytokines which increases glucocorticoids that affect thymus size
what causes ACUTE thymic atrophy?
loss of immature thymocytes (DP and DN) due to inflammation or stress
effect on thymocytes with chronic vs acute infection
inflammatory cytokines causes reduction in cytokines in chronic and acute cases but acute can recover
if acute injuries are affecting progenitors, what can happen when the stimulus stops?
get new progenitors from BM that seed the thymus and reconstitute the T cells
how does reconstitution of thymus change with age?
slower with age
why do chemotherapy patients also receive bone marrow transplants?
chemotherapy depletes hematopoietic cells and their progenitors –> BM transplant reconstitutes these populations
regarding BM transplant, what determines the outcome?
time btwn BM transplant and T cells coming out of thymus
what happens if there is a large gap btwn when BM is transplanted and T cells exit the thymus? (4)
there are fewer T cells, so can lead to:
1. cancer relapse
2. development of secondary malignancies
3. re-activation of latent infection
4. new infections
how does the gap btwn BM transplant and T cell regeneration change with age?
gap increases with age
4 possible treatments for boosting thymus function after acute damage
- sex steroid inhibitors
- IL-7 treatment
- soluble factors that help TEC function
- recall the beads with notch to make T-lineage committed progenitor cells
why can IL7 be used to treat acute thymus damage?
stimulates proliferations of progenitor T cells
