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44 Cards in this Set

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What is DiGeorge Syndrome?
DiGeorge syndrome is caused by a large deletion produced by error in Chromosome 22.
Symptoms: heart defects and recurrent infection due to absence of the thymus.
T cell deficiency and severe immunodeficiency.
Besides DiGeorge Syndrome, name another genetic disorder that proves that the thymus is the organ in which T cells develop.
Mutation in FOXN1 gene (chromosome 17)
FOXN1 encodes a trxn factor that is essential for the fx maturation of thymic epithelial cell progenitors.
Thymus gland fails to form in uteru and leads to T cell deficiency.
When in fetal development does the thymus form?
The thymus is essential for the initial establishment of the peripheral T cell pool in animals and humans.
Develops early in fetal development -> 7-8weeks of gestational age
By birth the peripheral T cell repertoire is established to the point that thymectomy does not cause immediate deficiency.
Cellular Composition
Stroma composed of fibroblasts and thymic epithelial cells (TEC).
TEC are derived from endoderm, produces IL1, IL6, IL7, SCF, TSLP required for growth and proliferation of immature T cells.
Where are Macrophages and DC cells found in the thymus. What do they do?
Macrophages and dendritic cells mature from the bone marrow and migrate into the thymus. Highly populate the cortical-medullary junction.
How do Thymoctyes get to the thymus and what do they become?
Thymocytes are the predominate cell type in the thymus, derived from progenitor cells of the bone marrow, the hematopoietic stem cells (HSC). After arriving in the thymus, bone marrow HSC become maure T cells, Treg and NKT.
How do T cells develop from HSC?
HSC in the thymus express CD34 and have the ability to become T cells as well as B cells, DC cells and NK cells.

Once HSC CD34+ starts migrating at 7-8 gestational weeks and enters the thymus it has chosen the path of T lineage -> CD34+ cells restricted to T lineage.
As you age you make less T cells.
What are the 4 stages of T cell development?
① T lineage commitment -> CD34+ restricted
② Proliferation and differentiation -> expansion of selected cells
③ Selection: + and - ➮ gaining of new surface markers
④ Maturation -> gaining of immune functions
How do HSC become commited to T cell lineage?
1) CD34 HSC leaves bone marrow goes to Thymus can become T cell/B cell/DC/NK cell.
2) Notch signal causes T cell to become commited to T cell lineage, express CD1A and begin to arrange TCR γ,δ and β genes. This is pre-T1 stage.
What occurs in the T cell development during the Pre-T1 stage?
Committed to T lineage
rearrangement of γ,δ and β genes
CD34+ AND CD1A+
What occurs in the T cell development during the pre-T2 stage?
Pre-T2 stage
Cells express CD4
Express preTα and TCRβ forming preTCR complex
preTCR allows pre-T2 cells to undergo β selection
TCRβ rearranged genes are examined and nonfx ones die and fx servive the β selection, proliferate and expand. This expansion of this stage is responsible for generating the large # of thymocytes with TCRαβ in the thymus. CD3 expression is also induced.
What determines whether a pre-T2 cell becomes a CD4 or CD8 T cell?
Selected pre-T2 progress into the double positive cells and begin to rearrange TCRα their rearrangement deletes TCR δ which is within then.
Depending on the signal via the co-receptor CD4 or CD8 surface molecules, DP cells down regulate one co-receptor and mature into single CD4 or CD8 T cells.
Describe the germline gene configureation for T cells.
β genome has V D and C like B cells.
α genome has V, J and C gene segments with δ genome embedded between the V and J segments
What are the stages of gene rearrangement in α:β T cells
β-chain locus rearranges first in CD4-CD8- double negative thymoctyes expressing CD25 and low levels of CD44.
-D to J gene segments rearrange before V gene segments rearrange to DJ to form VDJ.

Next the productively rearrange gene is expressed initially within the cell then at low levels on the cell surface
It associates with pTα, a surrogate similar to lamda 5 in B-cell dev.

pTα:β heterodimer froms a comlex with CD3. Expression of pre-T-cell receptor signals to stop β chain gene rearrangement and to undergo multiple divisions.
After proliferation CD4 and CD8 are expressed, cell ceases cycling and α chain rearrange deleting δ.

Last step: a functional α chain is produced that pairs efficiently with the B chain the CD3low CD4+CD8+ thymocyte is ready to undergo selection.
describe in detail the Dβ-Jβ rearrangement
Dβ-Jβ rearrangement causes DJ joining deleting intervening segments.
Vβ-DJβ rearrangement in frame. This produces a joining of VDJ
The resulting cells has CD25+ CD44 at low levels. Produces a pre-T1 cell that desplays CD34+CD1A+
how does rearrangement occur in the pre-T2 stage
Surface expression of β chain with surrogate α chain
β rearrangement stops
Cell proliferates
CD4/CD8 induction
α transcription starts
This is the pre-T2 stage
what occurs during Vα-Jα Rearrangement
Vα-Jα Rearrangement
surface expression of α:β:CD3
selective events begin
Double positive cell stage
What regulatory molecules are involved in regulatory negative selection?
Cells in the double positive stage withe functional TCRαβ/CD3 complex muste recognize self peptides in MHC I and II presented by cortical thymic epithelial cells.
this interaction must be low affiinity to be rescued from apoptosis. If they bind to self with high affinity they are negative selected ie killed because they are nonfx. Fx cells up-regulate expression of CD69 and shut down RAG1 and RAG2-> RAG=Recom Activation Genes
What would happen if IL7 is mutated
Expression of IL 7Rγ chain have SCID X1
a disease mutation of 1 receptor that makes IL 7 receptor
causes mutaion of IL7
lead to defect in B and T cell rearrangement.
Is there allelic exclusion in TCR Vα rearrangement
No allelic exclusion in TCR Vα rearrangement
How is T cell development affected by bone marrow transplant
Patients who receive bone marrow transplant generate T cells that recognize foreign antigens in the context of their own ie the recipient's MHC antigens indicating that developing donor T cells occurs on TEC of the patient recipient.
That means the T cells development occurs in the recipients thymus not in the donors bone marrow.
Why is negative selection necessary?
to generate central tolerance so that T cells do not recognize self-antigen as the enemy.
what is the mechanism of negative selection
Double positive cells with TCRαβ/CD3 complex that display high affinity for self-peptide and MHC are instructed to undergo apoptosis to eliminate T cells that would react with self and establish tolerance.
Where does negative selection occur?
negative selection occurs in the cortical-medullar region where a high density of thymic DC cells is present.
DC cells are also responsible for phagocytosis of apoptotic cells.
What is the fx of AIRE?
TEC also participate in clonal deletion of T cells that are reactive to organ specific antigens. AIRE - Autoimmune Regulator Element gene encodes a trxn factor that induces expression of a battery of peripheral tissue antigens in thymic medullary epithelial cells
AIRE promotes central tolerance by inducing negative selection prevent autoimmunity
what is the result of AIRE mutations
AIRE mutations are responsible for the development of autoimmune diseases
what causes CD4+ and CD8+ to mature
DP cells survive both the positive and negative selection processes will commit to either signle CD4+ or CD8+ cells
Selection of CD4 co-receptor and MHC-II will generate CD4 cells
CD8 coreceptor and MHC-I will generate mature CD8 cells
where are Mature CD4 and CD8 cells and where do they go when they mature
Mature CD4 and CD8 cells are predominantly resided in the medulla of the thymus
Mature CD4 and CD8 cells egress the thymus via blood vessels in the septa in the cortico-medullary junction
How does TCRγδ T cells develop
TCRγδ T cells develop from the Pre-T2 cells
the expression of pTa and signaling of this receptor skews cells toward TCRaβ lineage.
TCR γδ vs TCRaβ T cell:
TCR γδ vs TCRaβ T cell:
are predominantly CD4- and CD8-
TCR γδ receptor bind antigens directly
no antigen presentation required
TCR γδ repertoire is of two kinds
1) cells that express δ1 with various γ genes. δ1 cells are mucosal tissues
fx: lyse stressed/transformed epithelial cells
2) TCRγ9δ2 are majority of circulatory γδ T cells
fx: immunoregulation thru production of IFNγ which causes cytotoxicity and TGFβ also generates TH1.
Describe NKT development
NKT development
NKT develop in the thymus from CD4+CD8+DP thymocytes
NKT express both NK marker CD56 and TCRaβ/CD3 complex
DP that recognize glycolipid antigens presented by CD1D+ cortical thymoctyes became NKT cells
How are NKT cells stimulated to mature
NKT are either CD4+ or CD4-CD8-
most NKT express the Va24 and JaQ in association with various Vβ chains.
Mature NKT egress the thymus and populate: liver, spleen, BM, lymph nodes
Human NKT makes up .2% of peripheral blood T cell compartment
What is the function of NKT cells
NKT fx
NKT cells RAPIDLY produce TH1 (IL2, IFNγ) and TH2 cytokines (IL4, IL5, IL10, IL13) upon triggering thus they play a role in immunoregulation.
how are NKT related to human diseases
NKT and human diseases

IL4: NKT cell regulate autoimmunity in type I diabetes (IDDM) and MS.
What are the 4 CD1 proteins
Human CD1

4 proteins: CD1A, CD1B, CD1C and CD1D each on diff genes
What are CD1 proteins and what do they do?
CD1 proteins are transmembrane proteins that are distantly related to MHC molecules
CD1 lacks polymorphisms
what is the fx of CD1B and CD1C
CD1B and CD1C are noncovalently associated with β2m and known to present microbial glycolipid antigens
compare dominant tolerance to central tolerance
Treg
Thymus generates CD4+CD25+ suppressor cells with specificity for autoreactive T cells that may escape negative selection
This mode of suppression of autoreactivity is referred to as DOMINANT tolerance in contrast with cenral tolerance in which the autoreactive T cells are deleted.
Where and how does Treg development occur?
Treg Development
-in thymus from CD3+CD4+ T cells as early as 14 weeks of gestational age
how is Treg suppressed
Modes of suppression of Treg

-direct by inhibiting the upregulation of co-stimulatory molecules MHC-II, CD40, CD80/CD86 therefore preventing the activation of CD4+ T cells and the production of IL2 by the CD4 T cells

-directly suppress CD8+ activation and the production of IFNγ and IL2 by these cells
what is IPEX?
cause?
Treg and Human diseases

IPEX is a clinical syndrome that presents with multisystem autoimmune disease
IPEX patients lack Treg which is encoded by the FOXP3 gene on chromosome Xp11.23-Xq13.3 and encodes a transcription factor.
Expression of FOXP3 in CD4+ T cells is required for the development of Treg in the thymus.
What Tregs develop on the periphery?
Treg that develop in the periphery:
* Treg can be generated from peripheral mature CD4+ T cells by TGFβ
* Tr1
* Th3
What is the fx of IL1, IL6, IL7
IL1- in conjunction with IL3 and IL6, promotes proliferation of PHSC, CFC-GEMM and CFC-Ly

IL6- in conjunction with IL1 and IL3, it promotes proliferation of PHSC, and CFC-Ly; also facilitates B-cell differentiation into plasma cells.

IL7-promotes differentiation of CFC-Ly; enhances differentiation of CFC-T/NK cells and maturation of CFC-B to pro B cells.
What is the fx of
IL2
IL4
IL10
IL-2 stimulates activate T- and B-cell mitosis; induces differentiation of NK cells
IL-4 stimulates B-cell activation and development of mast cells and basophils. Also stimules DC development
IL10 a TH2 cytokine produced by NKT cells