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What tissues are central (primary) lymphoid tissue?
thymus and bone marrow; development sites of the cells of the adaptive immune system (B and T cells)
All hematopoietic cells arise from precursors in the bone. What are the lineages?
- 1. lymphoid
- 2. myeloid
- 3. erythroid
Where d B cells undergo development?
In the bone marrow
A B-cell that expresses a functional B-cell receptor, implies successful_____.
somatic recombination (catalyzed by proteins encoded by RAG) of germ-line Ig heavy and light chains.
Where does B-cell somatic recombination occur?
In the bone marrow
Where do B cells migrate to become mature naive B cells?
secondary lymphoid tissues (lymph nodes, spleen, tonsils, mucosa of lymphoid tissue)
T cells migrate to the thymus to complete their development to become naive T cells, but where are they "born"?
in the bone marrow
What ensures that T cells are capable of recognizing peptide:MHC complexes?
development in the thymus; T cells become "tolerant" to self-peptide:MHC complexes, and will not attack
Just like B Cells, a T cell must express functional T cell receptors, which implies successful________.
somatic recombination (catalyzed by encoded RAG) of germ-line TCR chain genes
Somatic recombination for B cells occurs in the_______ but somatic recombination for T cells occurs in the________.
in the bone marrow for B cells; in the thymus for T cells
Where is the thymus located?
slightly above and anterior to the heart
What does the thymus consist of?
each lobe consists of a cortex (the outer peripheral) and a medulla (the central core area)
Epithelial cells of thymus origin are referred to as...
Cells of bone origin that end up in the thymus are referred to as
immature T cells (thymocytes)
What is the only way lymphocytes enter and leave the thymus?
ONLY via bloodstream ( NEVER via lymphatics)
What is the thymus required for?
T cell development
What happens if you have no thymus?
no functional T cells, leads to no adaptive immune response (sense CD4 helper T cells are needed to stimulate adaptive B cells to extracellular infection)
What is DiGeorge's Syndrome?
What are the consequences of this illness?
A genetic disease where there is a failure of the thymus to develop
no thymus, no functional T cells, no adaptive immune system; leads to SCID (severe combined immunodeficiency disease)
Why is DiGeorge's Syndrome (SCID), most important during the fetal stage, infancy, and early childhood?
Very young children do not have a competent immune system yet; without a properly functioning thymus, will not be able to fight off infections effectively
may elect to do a bone marrow transplant and supportive therapies.
In regards the the thymus, what is "involution"?
the process of thymus tissue being gradually replaced by fat as we age (a normal process)
Does the removal of the thymus in adults have a large effect on T cell mediated immunity?
Progenitor cells are NOT committed to becoming T cells until AFTER...
they enter the thymus
What cells do progenitor cells interact with before becoming thymocytes?
thymic stromal cells
What do thymic stromal cells secrete that bind to the receptor on progenitor cells, that is a required interaction for T cell development?
Other than cytokines, what else do the thymic stromal cells present?
Thymic stream cells express a notch ligand that progenitor cells have a notch receptor for
which after binding, leads to transcription signaling to the nucleus
Which constitutively active protein molecule is found in half of all adult T cell leukemias?
What are the two possible types or TCRs
α:β and γ:δ
A functional α:β chain dimer expresses, and recognizes what?
expresses an α:β TCR and recognizes peptide:MHC
A functional γ:δ chain dimer expresses what, and recognizes what?
expresses γ:δ TCR but does NOT require antigen processing or MHC to recognize its ligand
When does the first gene rearrangement in TCRs occur?
If successful, what does it lead to?
in double negative thymocytes (not expressing CD4 or CD8)
can lead to either γ:δTCR assembly or pre-TCR assembly
What is gene rearrangement of germ-line DNA coding for TCRs catalyzed by?
RAG recombinase proteins
How can β, γ, and δ undergo rearrangement simultaneously?
β and δ both have V, D, and J segments; γ has V and J segments
What determines γ:δ or α:β(pre) TCR?
Which ever is successfully rearrange first
(note pre-TCR = beta chain + pTα + CD3 complex)
What happens during the first checkpoint development in the thymus, if T cell gene rearrangement does NOT achieve either γ:δ-TCR or pre-TCR?
thymocyte undergoes apoptosis and is removed from thymus by macrophage via phagocytosis
What does successfully passing checkpoint 1 imply in TCR development in the thymus?
- 1. γ:δ receptor was produced
- 2. pre-TCR was produced
What happens if a γ:δ receptor is produced in the thymus before it can form a pre-TCR?
becomes a γ:δ T cell and leaves the thymus
What happens if a is produced pre-TCR in the thymus before it can form a γ:δ receptor?
The cell must form an α chain. As a pre-TCR, it already contains a β chain so rearrangement was achieved and RAG proteins were turned off leading to allelic exclusion.
T cells proliferated and now they express both CD4 and CD8 ON THE SAME CELL (resulting in double positives)
RAG is turned back on and rearrangement begins at the α-locus to make an α:β TCR
In what two ways can a TCR pass checkpoint 2?
1. productive rearrangement to produce an α-chain that can dimerize with a β-chain and displace pTα to yield an α:β TCR
2. productive γ and δ rearrangements that yield a γ:δ TCR
What happens if Pre T cell fails to pass checkpoint 2?
Where does positive selection of α:β T cells occur?
What does positive selection do?
in the cortex of the thymus
tests the ability of α:β T cells to recognize peptide:MHC complexes
Where other than bone are MHC class II expressed?
thymic epithelial cells
What do peptide:MHC complexes on thymic epithelial cells contain and what is its purpose?
self peptide which allow double positive α:β thymocytes to test their TCRs for capacity to bind peptide:MHC complexes
these double-positive thymocytes require a survival signal generated from the thymic epithelial cells to survive or will undergo apoptosis
if successful receptor editing occurs in original α-chain leading to a productive α:β TCR NOT capable of recognizing peptide:MHC, it can survive
How are single-positive thymocytes generated?
if a TCR binds better to a self-peptide:self-MHC class I complex on the thymic epithelial cell, CD8 is recruited to the binding interaction and sends signal to the nucleus of thymocytes to turn off CD4 expression so only CD8 will be produced
and the same process only vice versa with CD4 and it involves MHC II instead
What happens if an organism has defective MHC I expression?
CD8 T cells will not be produced but CD4 will
vice versa for CD4; similar process but defective MHC II will allow for only CD8 to be produced
During negative selection α:β cells are destroyed in the thymus if found to be self reactive. How?
Dendritic cells and macrophages present antigens to these TCRs. If it binds too tightly (high affinity) to a self-peptide:self-MHC complex, the thymocyte will be signaled for apoptosis
if it binds moderately, the thymocyte is signaled to survive
Thymocytes also extend negative selection to other proteins that may be tissue specific such as...
insulin which is not normally in lymphoid tissue
How do CD4 helper T cells play regulatory role?
can help induce and maintain tolerance by sending out a suppression signal if it binds to a sec-peptide:self:MHC complex