Chapter 7: Development Of T Lymphocytes Flashcards
T cell precursor migrate from the…
- bone marrow to the thymus to mature
Mature T cells leave…
- the thymus in the blood, from where they enter secondary lymphod tissues and then return to the blood and the lymph
The cortex consists of…
- immature thymocytes
- branched cortical epithelial cells
- few macrophages
The medulla consists of…
- mature thymocytes
- medullary epithelial cells
- dendritic cells
- macrophages
One functions of the macrophages in both the cortex and medulla is to…
- remove the thymocytes that fail to mature properly
The human thymus is fully developed before birth and as a person ages…
- the thymus begins to degenerate and replace with fatty tissue
Thymocytes commit to the T-cell lineage before rearranging their T-cell receptor genes. When entering the thymus they become…
- CD34+
After a week of interaction with the ____________ ______________ cell, these stem cells differentiate and lose their stem cell markers.
- thymus stromal
Commitment to the T-cell lineage involves changes in ______ _____________ and in cell-surface markers
- gene expression
Cells are called ________ _________ thermocytes do not express CD4 nor CD8
- double negative
IL-7 first critical cytokine important in…
- development of T cells
What is Notch 1?
- major regulator of T cell development
- helps in transcription of gene necessary for T cell development
T-cell development is driven by the receptor…
- Notch 1
Activity of Notch 1
- Notch 1 on the thermocyte binds to its ligand on thymic epithelial
- this induces a protease to cleave the intracellular domain from the PM
- the soluble intracellular domain is translocated to the nucleus, where is turns on the expression of genes essential for T-cell development
- removal of repressive transcription factors and recruiting co-activating transcription factors
Two lineages of T cells arise from a…
- common thymocyte progenitor
ALPHA:BETA and GAMMA:DELTA develop from a…
- common double-negative T-cells progenitor
T-cell precursor that enter the thymus express the hematopoietic stem cell marker ______ but none of the characteristic markers of mature T cells
- CD34
Proliferation of these common progenitors followed by ______________ of the delta-, gamma- and beta-chain genes, which leads to early commitment of some cells to the gamma:delta T-cell linage, whereas others rearrange the _________ chain gene first and temporarily halt _____ ________ at this point.
- rearrangement
- beta
- gene rearrangement
Once a complete gamma:delta receptor is created the T cells…
- leave the thymus and travel to other tissues via the blood
The beta-chain-positive cells in the thymus, rearrangement of the alpha-, gamma-, and delta chain genes resumes productive alpha-chain gene rearrangements in these cells producing a ___________-___________ __________ __________ alpha:beta cells
- double-positive
- CD4
- CD8
Minority of double-positive thymocytes give rise additional gamma:delta T-cells. This ends…
- the early stage of alpha:beta T-cell development
Alpha:Beta and Gamma:Delta T-cells develop from a common ___________-____________ T-cell ________________.
- double-negative
- progenitor
Gene rearrangement…
- in double-negative thymocytes leads to assembly of either a gamma:delta receptor or a pre-T-cell receptor
T cells can can also make productive and nonproductive gene rearrangent
- like immunoglobulins
There are _____ chromosomes for each of the _____ locus
- two
- two
Beta and Delta chains are like _______________ heavy chain and contain _______ segments, where as alpha and gamma are like the immunoglobulin LC containing ________ segments.
- immunoglobulin
- VDJ
- VJ
For beta and delta:
- first rearrangement joins the DJ
- second rearrangement joins the V to the DJ
For alpha and gamma…
- single rearrangement joins V to J
Alpha (alpha) chain gene rearrangement occurs…
- last
By the way, alpha chain which is like an Ig LC has surrogate (pT-alpha) to test the productive beta chain protein in the…
- Endoplasmic Reticulum
If the beta chain bind pT-alpha, the heterodimer assembles with the CD3 complex. This assembly is called the…
- pre-T-cell receptor
Thermocytes can make _________ attempts to rearrange a beta-chain gene
- four
What is the successive rate of producing a beta chain gene rearrangement?
- 80%
Non-productive gene rearrangement can be rescued __________ in the same loci, thus up to 4 chances. There are only 2 chromosomes.
- once
Rearrangement of the alpha-chain gene occurs in pre-T cells. No pre-T cell, ____ ______________ of the alpha chain gene
- No rearrangement
Once a successfull B chain is made (gotta get checked with the surrogate alpha chain, pT-alpha), then the pre-T cell stops the RAG1 and RAG2
- no further rearrangement goes on with beta
- proliferation then occurs (takes place)
The first two molecules made are double positive cells are…
- CD4 and CD8
Alpha chain gene rearrangement can start when?
- when the the first CD4 and/or CD8 molecules are made
What happens to delta chain gene?
- gets deleted in the process cause within alpha chain DNA
Rescue of unproductive rearrangements of the beta-chain locus only if…
- that rearrangement involves D and J gene segments associated with the C-beta-1 gene segment
- then the second rearrangement is then possible where the V-beta gene segment rearranges to a DJ segment associated w/ the C-beta-2 gene segment, deleting C-beta-1 and the unproductively rearranged gene segments
Successive gene rearrangements allow the replacement of one T-cell receptor alpha chain by another.
- multiplicity of V and J gene segments allow successive rearrangement events to jump over unproductively rearranged VJ segments, deleting the intervening gene segments
- this process continues until either a productive rearrangement occurs or the supply of V and J gene segments is exhausted, where the cell will die
Stages in T-cell development are marked by changes in _____________ expression
- gene
Once a developing thymocyte expresses an alpha:beta receptor and CD4 and CD8 on its surface, it undergoes two types of selection:
- positive and negative
Both types of selection involve testing the receptor’s interaction with the complexes of self peptides bound by self-MHC molecules on the surfaces of thymic cells. We focus on the _______:_________
- alpha:beta
T cells that recognize ______-______ are positively selected in the _____________ (cortex)
- self-MHC
- thymus
Positive selection
- process whereby a small subpopulation (2%) is selected and signaled to mature further
- the vast majority of double positive (CD4, CD8) T cells (98%) die by apoptosis in the thymic cortex
Mechanism of positive selection
- T-cells w/ a T-cell receptor (TCR) that binds to a self-MHC class 1 molecule on thymic cortical epithelial cells, macrophages, and other cells in the thymus are signaled to survive and proceed to negative selection
- T-cells w/ a TCR that binds to no self-MHC class 1 molecules are signaled to die (APOPTOSIS)
- same is true for self-MHC class 2
Continuing alpha-chain gene rearrangement increases the chance for ________________ selection
- positive
- first alpha chain gene rearrangement that a pre-T cell makes is productive and leads to the assembly of an alpha:beta TCR that interacts w/ a self self-MHC molecule positive selection will occur within a few hours
The T cells is then signaled to turn off the RAG genes and ____________________ machinery.
- recombination
- cell then enters a phase of proliferation
If the TCR does not bind a self-MHC molecule, _____________ of the alpha chain continues until 3-4 days to improve its chances of having a binding site that bind MHC molecules.
- rearrangement
- there is no allelic exclusion in alpha chain rearrangement, unlike the beta chain
Positive selection determines expression of either the _______ or the ________ co-receptor
- CD4
- CD8
Double positive becomes a…
- single-positive thymocyte
During positive selection, the double positive will interact through its ______:______ receptor with a particular peptide: ________ complex
- alpha:beta
- MHC
- when interacting MHC molecule is class 1, CD8 molecules are recruited into the interaction (CD4 is excluded)
- when interacting MHC molecule is class 2, CD4 molecules are recruited and CD8 are excluded
Negative selection of the T cell repertoire can be also called…
- central tolerance
T cells specific for self antigens are…
- removed in the thymus by negative selection
Negative selection deletes by ______________ T cells whose antigen receptors _________ __________ __________ to the complexes of self peptides and self MHC molecules presented by cells in the thymus.
- apoptosis
- bind too strongly
T cells are autoreactive and if allowed to enter the peripheral circulation they could cause damage and autoimmune disease describes…
- negative selection
Positive selection is mediated exclusively by epithelial cells in the cortex of the thymus, negative selection can be mediated by several cell types which are…
- dendritic
- macrophages
- thymocytes
Where do these self antigen come from in order to participate in negative selection?
- tissue-specific proteins are expressed in the thymus
Autoimmune Regulator (AIRE)
- caused several hundred of these self antigen to be expressed by epithelial cells in the medulla of the thymus
Peripheral Tolerance
- like autoreactive B-cells that barely graduate the bone marrow, T cells undergo anergy
Autoreactive T-cells are suppressed by _________ T regulatory cells
- CD4
- regulatory CD4 T cells comprise a distinct lineage of CD4 T cells
- suppression of an autoreactive CD4 T cells by a regulatory T cell is dependent on the interaction of both T cells with the same APC
Treg cells are specific for…
- self antigens
T reg cells have ________ on its surface, unlike other CD4 T cells
- CD25
