Development of T Lymphocytes Flashcards
When does the thymus develop?
Very early during: the epithelial component begins to develop during the 4th week
What immune cells develop in the thymus?
T helper
Cytotoxic T cells
Natural Killer
T regulatory
From which pharyngeal pouch does the epithelial component of the thymus develop?
Third
At what week does the developing thymus begin to produce T cells?
12th-13th week
Mature T cells begin to egress the thymus during the 13th-14th week
What is DiGeorge Syndrome? What does it tell us about the thymus?
Rare congenital disease syndrome whose symptoms vary greatly between individuals but commonly include a history of heart defects, characteristic facial features and recurrent infection due to absence of the thymus and T cells
The absence of the functional thymus results in complete T cell deficiency and severe immunodeficiency- transplantation of an allogeneic thymus graft into patients rescues T cell deficiency.
This suggests that the thymus is required for proper T cell maturation
What other genetic disease affects proper T cell development?
FOXN1 mutations
Which cells make up the thymic stroma?
Thymic epithelial cells and fibroblasts
Where in the thymus are mature T cells found?
Medulla
Where in the thymus are developing T cells found?
Cortex
Where in the thymus are the blood vessels containing HEV’s found?
Cortical-medullary junction
Thymic epithelial cells provide what three critical functions for T cells?
1) Produce cytokines such as IL1, IL6, IL7 and SCF, TSLP that are required for growth and differentiation of various immature T cells
2) Expression of molecules such as ligands DL-4 and DL-1 for the notch receptor, required for T cell lineage development
3) Expression of MHC classes I and II controlling the selection of maturing T cells
All thymic epithelial cells are derived from what germ layer?
Endoderm
Where do macrophages and dendritic cells mature?
Bone marrow
Where are macrophages and dendritic cells found in high populations in the thymus?
Cortico-medullary junction
What is the role of macrophages and DCs in the thymus?
antigen presentation, deletion of autoreactive T cells (negative selection) and phagocytosis of apoptotic thymocytes
What marker is indicative of HSCs?
CD34
Upon entry to the thymus, how is the lineage potential of CD34 pos. cells restricted?
CD34 positive can ONLY become T cells once they enter the thymus
How does the activity of the thymus relate to the decline in immune response of the elderly?
The age-associated decline in the production of T cells is responsible for the decline in immune response in the elderly
Describe the role of Notch signaling in T cell development
The Notch receptor signal is essential for T cell lineage commitment of the CD34 positive HSC.
Signal through the notch receptor terminates the potential to commit to B and myeloid lineages (monocytes and DC). The cells have potential to become T or NK cells (T/NK). Persisting notch signaling terminates NK development.
What is the role of DL-1/DL-4? What cells express it? What cellular events occur in the developing T cell?
DL-1/DL-4 is the notch receptor ligand, expressed by the thymic epithelial cells.
Following notch signaling, cells commit to the T lineage, through the rearrangement of TCR gamma, delta and beta genes.
What can a developing T cell develop into following notch signaling?
Following notch signaling, preT cells may develop into either TCR gamma/delta or TCR alpha/beta cells.
This rearrangement of gamma, delta and beta genes requires the expression of RAG 1 and RAG 2
Which cytokine is required for the development of the preT stage?
IL-7
In the immature single positive stage of T cell development, the expression of preT alpha induces the expression of what other membrane protein?
CD3
What is the pre TCR complex? What stage of development is it expressed?
TCRbeta and pre T alpha
Expressed in the immature single positive CDISP
Are the majority of T cells part of the alpha/beta lineage or gamma/delta lineage?
alpha/beta
Describe the beta selection process
The expression of the pre TCR (beta/preTalpha) allows the ISP cells to undergo the beta selection process. This process selects cells with productive rearranged TCRbeta genes signaling via the preTCR.
Cells that do not signal through the preTCR are killed via apoptosis.
Cells that survive the beta-selection process step proliferate and expand.
The enormous expansion of cells at what stage is responsible for generating the large number of thymocytes with TCR alpha/beta in the thymus?
ISP cells: immature single positive cells expressing preTCR
During what stage is CD3 up-regulated?
ISP
What is the “single positive” in immature single positive cells?
CD4 is expressed
What happens to cells that are selected to progress from CD4+ ISPs?
They express CD8 and are now double positive
When does TCR alpha rearrangement occur? What is deleted during this process and why?
During the DP stage.
Because the TCR delta locus is within the TCR alpha genes, rearrangement of the TCR V alpha genes will delete the delta locus.
Discuss allelic exclusion for the TCR V alpha genes (variable)
There is none- there can be two different rearranged V alpha chains, each associated with a common V beta
How does the developing T cell “decide” to become CD4 or CD8 + T cells?
Depending on whether the T cells binds with Ag-MHC class I or MHC class II (presented by cortical TEC), the T cell will downregulate the unbound receptor, and upregulate whatever co-receptor binds to the MHC:antigen complex
Describe the quality of binding necessary for positive selection/ rescue from apoptosis of DP T cells
DP cells with LOW affinity binding for self peptides are rescued from apoptosis and are able to proliferate.
These cells shut down the expression of RAG so that no more rearrangement takes place (there is no somatic hypermutation in T cell development)
What happens to DP T cells that do not recognize self peptides?
They undergo apoptosis
Do patients who receive bone marrow transplants generate T cells that recognize foreign antigens in context of their own MHC or the donor MHC?
Developing donor T cells occurs on the TEC of the patient recipient, not the donor
What is the purpose of negative selection in the development of T cells?
Generation of central tolerance: via deletion of mature T cells that bind strongly to MHC/antigens (autoreactive T cells)
Where does negative selection occur?
Predominantly in the corticomedullary region where a high density of thymic DC cells is present
What is AIRE responsible for?
Auto Immune Regulator Element (AIRE) gene encodes a transcription factor that induces expression of a battery of peripheral-tissue antigens by thymic medullary epithelial cells
THUS: AIRE promotes central tolerance of thymocytes by inducing negative selection, contributing to the prevention of organ specific autoimmunity.
What is APECED/APS1? What organs are affected?
Diseases associated with AIRE deficiencies.
APECED: fungus on tongue/toes
Affected organs are adrenal, thyroid, parathyroid and pancreas
How do mature CD4+ or CD8+ cells leave the thymus?
Blood vessels in the septa of the corticomedullary junction
What is the general CD4 and CD8 status of TCR delta/gamma cells?
CD4 and CD8 negative
How do TCR gamma/delta cells bind antigen?
They bind antigen directly- no antigen presentation by MHC Class I /class II is required
What are the two dominant TCR gamma/delta cells?
1) Cells that express delta1 with various gamma genes. They are the first gamma/delta T cells that emerge from the fetal thymus and populate epithelial tissues such as the intestine and skin. They recognize stressed cells and lipid antigens presented by CD1B or CD1C molecules
2) TCRgamma9delta2: 80% of circulatory gamma/delta T cells
What are the four CD1 proteins?
These are transmembrane proteins distantly related to MHC molecules
There are 4: CD1A, CD1B, CD1C and CD1D
CD1B and CD1C noncovalently associated with what protein?
beta 2 microglobulin (which associates with MHC class I alpha)
CD1B, CD1C and CD1D bind to what?
glycolipid antigens
What is the function of TCR delta 1 cells?
They lyse stressed/transformed epithelial cells
What is the function of TCR gamma 9 delta 2?
recognize non-peptide pyrophosphomonoester antignes found on micobacterium and malaria
These cells also kill intra and extracellular m. tuberculosis, produce INFgamma that affects the cytotoxicity of NK and NKT cells and the generation of Th1 cells
Natural Killer T cells develop from what precursor?
NKT cells develop in the thymus from common lymphoid progenitor
DP that recognize glycolipid antigens presented by CD1D positive cortical thymocytes develop into what type of cell?
NKT
What are the markers on NKT cells?
NKT cells are either CD4+, or CD4/CD8 double negative
What is the NKT marker?
CD56
Mature NKT cells leave the thymus and enter which tissues?
liver, spleen, BM and lymph nodes
What is the primary functions of NKT cells?
NKT cells rapidly produce both Th1 (INF-gamma) and Th2 cytokines (IL4, IL5, IL10) upon activation
What is dominant tolerance?
In contrast to central tolerance (in which autoreactive cells are deleted) dominant tolerance is the process by which the thymus generates CD4+ CD25+ suppressor cells with specificity for autoreactive T cells that may escape
