T Cell Maturation Flashcards
What kind of T cells can HSCs develop into?
- NK T cells
- T Regulatory cells
- Cytotoxic T cells (CD8+)
- Helper T cells (CD4+)
Describe the development of the thymus in utero.
Week 4-7: Derived from the pharyngeal pouch, the thymic gland breaks off bilaterally and travels to the mediastinum. Forms a single bilobule pouch
Week 7: colonization by HSCs
Week 12: production of T cells
Week 13: mature T cells egress
birth: large repertoire of peripheral T cells
Describe DiGeorge Syndrome (AKA?)
AKA velo-cardio-facial syndrome (VCFS)
- due to deletion of chromosome 22
- symptoms = no hair, characteristic facial features, heart defects, recurrent infection
- manifestation = no thymus, no T cells
- severe immunodeficiency
- tx = thymus graft transplant
Describe FOXN1 mutation.
- FOXN1 gene on chromosome 17
- normal function = encodes a transcription factor essential for TEC development
- mutation = CGA => TGA (stop codon)
- in utero, immature epithelial progenitors form cyst-like thymus, cannot recruit HSCs
- symptoms - immunodeficiency
- tx - thymus transplant
What kind of cells make up the thymic capsule?
fibroblasts
What kind of cells make up the thymic cortex?
developing T cells, some macrophages, cortical TEC
What kind of cells make up the thymic medulla?
mature T cells, macrophages/DCs, medullary TEC
What kind of cells make up the CMJ?
- macrophages and DCs
- entrance of thymocyte progenitors
What is the purpose of the cells in the CMJ?
- macrophages and DCs
- APC
- negative selection
- phagocytosis of apoptotic thymocytes
Which cells make up the thymic stroma?
- fibroblasts
- TEC
What are the kinds of TEC?
- cortical
- medullary
- Hassal’s
What are TEC derived from?
endoderm
What cytokines do TEC produce?
- IL-1, IL-6, IL-7
- stem cell factor (SCF)
- thymic stroma lymphopoietin (TSLP - used for Treg differentiation)
What surface markers do TECs have?
- Delta-like-1, Delta-like-4
(required for notch signaling and T lineage commitment) - MHC I and II (positive selection)
- peripheral tissue antigens (negative selection)
In what form do HSCs enter the thymus?
CD34+
via blood
What cell is the umbilical cord rich in?
CD34+
What happens to T cell proliferation after puberty?
- declines, but peripheral pool is maintained
What are the stages of T cell development?
- T lineage commitment
- Proliferation
- Differentiation
- Positive Selection
- Negative Selection
What are the cell stages of T cell development?
- progenitors
- pre-T
- ISP
- DP
- mature SP
Describe the mechanism of T cell lineage commitment.
- thymocyte progenitors from the bone marrow enter the thymus via blood
- Notch ligand on the progenitor interacts with DL1 or Dl4 on cortical TECs
- notch-delta signaling terminates possibility of other lymphoid lineages and commits cell to T lineage
Describe how a progenitor becomes a pre-T cell.
- after notch-delta signaling, committed progenitors express CD1A
- Through CD1A and IL-7, cell begins expressing RAG 1 and RAG2 and undergoes TCR-gamma, delta, and beta rearrangements
- expression of the pre-TCR complex (pTa, rearranged B chain, CD3)
Describe how a pre-T cell becomes an ISP.
- After pre-TCR complex is expressed, CD4 is expressed
Now it is an immature single positive cell
Describe ISP Beta selection stage.
- At this stage, the ISPs express CD3, CD4, and a pre-TCR complex
- Once a functional cell is selected => degradation of RAG to stop further beta chain rearrangement
- vigorous proliferation of the ISPs (huge increase in thymocyte numbers)
- increase expression of CD3
What is the purpose of ISP Beta selection?
The purpose of this stage is to positively select for functional B chains
How does an ISP become a DP?
- beta selected cells now express both CD4 and CD8
- re-expression of RAG induces alpha chain rearrangement (deletion of delta genes)
- mature alpha and beta TCR
What is unique about alpha chains in TCR?
no allelic exclusion
more than one alpha chain can bind to the same beta chain
thus, one DP might express multiple alpha chains
Describe the process of positive selection.
- cTECs express both self-MHC and self-peptide (peptide:MHC complex)
- If a DP binds to MHC Class I => downregulation of CD4+ => becomes a CD8+ T cell
- If a DP binds to MHC Class II => downregulation of CD8+ => becomes a CD4+ T cell
- If a DP does not bind OR binds too strongly => apoptosis (induced by CMJ cells and phagocytosed by those as well)
What is BLS?
Bare Lymphocyte Syndrome
- defect in MHC Class II expression
- cannot produce CD4+ cells
Why is positive selection important for bone marrow transplant recipients?
- the patient did NOT receive a thymic transplant.
- Therefore, the cTECs still express SELF-MHC
- donor bone marrow progenitors will be selected for based on affinity to self-MHC instead of donor-MHC
Describe the process of negative selection.
- mTECs encode AIRE, a transcription factor that induces expression of various organ-specific antigens
- T cells that bind with high affinity to the mTECs undergo apoptosis via CMJ or medullary macrophages/DCs
Define AIRE.
autoimmune regulatory element
TF that encodes a battery of organ-specific self antigens
Describe APECED.
autoimmune polyendocrinopathy candidiasis ectodermal dystrophy
- mutation in AIRE
- generation of several autoreactive T cells
- symptoms = candidiasis, candidal onychomycosis, vitiligo, halo neevi
- affected organs = adrenal, thyroid, parathyroid, pancreas
What are some AIRE mutations?
APECED
APS1
What do T-gd cells derive from?
ISP
What is unique about T-gd cells?
- double negative for CD4/CD8
- can bind antigens directly
- do not need MHC presentation
Describe T-gd1 cells.
- reside in epithelial tissue
- recognizes stressed tissues and lipid antigens present on CD1B or C
Describe T-g9-d2 cells
- circulating T-gd cells
- recognizes phosphor antigens found on mycobacterium and malaria
- immunoregulation
Define CD1
- related to MHC
- ABCD
- BC mostly bind to glycolipid antigens
Describe development of NKT cells.
- derived from DP thymocytes that recognize glycolipids:CD1D on cTECs
Describe surface markers of NKT cells.
- express both TCRab (T cell) and CD25+ (NK)
- can be CD4+ or double negative
Where do NKT cells reside?
- reside in spleen, lymph nodes, bone marrow
List NKT functions.
- immunoregulation Th1 cytokines (IFN-g, IL-2) => increases cytotoxicity of NK and killer T cells, increases macrophage phagocytosis, increases Th1 response
Th2 cytokines (IL-4, IL-10, IL-13) => increase Th2 response
Define dominant tolerance.
suppression of autoreactive T cells by Tregs instead of apoptosis (like by central tolerance)
What is the function of Tregs?
suppress autoreactive T cells that escaped from central tolerance
What do Tregs express?
CD4+CD25+
What cytokines are required for Treg development?
- derived from peripheral mature CD4+ T cells
- TGF-b
- TSLP (thymic stroma lymphopoietin)
- creates Tr1 and Th3
- FOXP3
Describe IPEX.
immune dsyregulation, polyendocrinopathy, enteropathy, x-linked
- multisystem autoimmune disease
- symptoms - diarrhea, insulin-dependent DM, thyroid, eczema
- due to FOXP3 defect
- lacks Tregs
What can abnormal Treg levels lead to?
too little = IPEX
too much = cancer
