T Cell Development and Diversity Flashcards
What is a T cell?
• derived from the common lymphoid precursor and bears a TCR
in context of MHC, what do T cells recognize?
• T cells ONLY recognize peptide antigens
T cells serve several important roles in acquired immune responses. What are they?
- • kill cells infected with viral or other intracellular pathogen
- • supply helper signals which activate B cells and macrophages
T/F T cells do not secrete immunoglobulin molecules
true
There are 2 lineages of T cells. Describe them
- most T cells bear a TCR composed of an α and a β chain; these are referred to as αβ T cells
- some T cells bear a TCR composed of a γ and a δ chain; these are referred to as γδ T cells
Describe γδ T cells wrt recognition, location, maturity, role)
- primitive cells that do not seem to recognize peptide/MHC complexes (not MHC-restricted)
- found primarily in mucosal epithelium
- mature extrathymically
- thought to have significant role in recognition of lipid antigens
What is the signal transduction unit for the T cell receptor? where is it found?
• CD3:
What is the role of ITAMS: immunoreceptor tyrosine-based activation motifs?
initiate signaling cascade upon antigen-recognition thru the TCR
What are Important Surface Markers of T cells?
- CD4 and CD8: co-receptors for the T cell receptor
- CD28
- Fas ligand
- adhesion molecules
describe the importance of CD4 and CD8 as co-receptors for the TCR
all mature αβ T cells express either CD4 or CD8
- • CD4 binds (weakly) to MHC class II molecules
- • CD8 binds (weakly) to MHC class I molecules
What molecule binds to B7 molecules on antigen presenting cells; (co-stimulation)?
CD28
Describe the surface T cell marker effect wrt to Fas ligand
it can bind to Fas expressed on the surface of target cells, initiating Fas-mediated apoptosis
What T cell surface marker can initiate interactions between T cells and APC or target cells?
adhesion molecules
Where are thymocytes produced? Where do they mature?
Thymocytes are Produced in BM,
Mature in Thymus
Thymocytes Interact with what type cell?
Thymic Epithelial Cells
What is the role of Tingible-body Macrophages?
Remove Apoptotic Cells
TCR Variable Region Gene Rearrangements. Which are the first to rearrange?
beta, gamma, and delta chain genes are the first to rearrange
if gamma and delta chain rearrangement is successful before beta chain rearrangement, what T cell forms?
T cell will be a γδ T cell
if beta chain rearrangement of the TCR variable region is 1st to be successful, what is the result?
it associates with an invariant chain (pTα; a surrogate alpha chain) and the CD3 complex to form the pre-T cell receptor complex
once the pre-TCR is expressed, what happens wrt gene rearrangement?
beta, gamma, and delta gene rearrangements cease
Describe somatic recombination of TCR genes
- pre T cell begins to proliferate
- alpha chain gene rearrangement begins
- if alpha chain gene rearrangement is successful, the expressed alpha chain polypeptide associates with nascent beta chain polypeptides and the final T cell receptor is expressed
Thymocytes that bind best to MHC class I will have what result?
Up-regulate CD8 expression
and
Down-regulate CD4 expression
Thymocytes that bind best to MHC class II will have what result?
Up-regulate CD4 expression
and
Down-regulate CD8 expression
Mature T cells Migrate where?
2˚ Lymphoid Tissues
Why is Somatic Recombination of TCR Ig Genes Such an Important Mechanism?
the TCR Ig genes code for up to 10^18 different TCR molecules
the human genome contains approximately 40,000 genes
Decreases the size of the genome required for the proper genes to include an adequate repertoire
What are the characteristic cell-surface markers and its location of a stem cell?
marker => CD34
location => bone marrow
What are the characteristic cell-surface markers and its location of a lymphoid progenitor cell?
markers => CD10, CD19, CD20
location => thymus
What are the characteristic cell-surface markers and its location of a thymic stromal cell or epithelial cell?
markers => cytokeratins
location => thymus
What are the characteristic cell-surface markers and its location of a thymocyte?
markers => CD1
location => thymus
What are the characteristic cell-surface markers and its location of a T cell?
markers => CD3/TCR and CD4 or CD8
location => periphery
What is a cell that differentiates into cells that either kill target cells that bear their cognate peptide:MHC class I complex, or supply help to other immune cells via production of cytokines?
T cell
How do T cells recognize specific antigen? Where must the antigen be bound to?
bound to MHC complex on APCs
recognize antigen via TCR
What is the T cell receptor?
disulfide-linked heterodimer that consists of either an alpha and a Beta chain
or a gamma and a delta chain
Both chains of the TCR have what regions?
constant region and a variable (hypervariable) region, resembling the light chains of Ab molecules
amino-terminal segment of each chain contains what?
the variable domain,
and the constant domain is near
Other than the constant domain, what else can be found at the C-terminus of the TCR? What is the purpose for this region?
hinge-like region followed by a transmembrane region and a short cytoplasmic tail
region of the TCR anchors it into the membrane of T cells and allows some flexibility of the molecule (hinge region)
the TCR resembles (structurally and functionally) to what type of membrane-bound antibody?
Fab fragment
T/F variable regions of the TCR complex are constructed by a mechanism very similar to that of immunoglobulin variable region genes.
true
Describe the relationship of the a cassette system and the V region of the TCR complex
A cassette system (containing many gene segments) is used to randomly generate a huge repertoire of TCR molecules that differ primarily in their V regions (somatic recombination).
there are two lineages of T cells that develop in the thymus that are defined by what?
the T cell receptor (TCR) that they express
- gamma/delta TCR
- alpha/beta TCR
T/F gamma/delta T cells may or may not express CD4 or CD8 markers
true
T/F gamma/delta T cells are not MHC-restricted in their recognition of antigen
true
Where are most gamma/delta T cells found?
mucosal epithelium
T/F gamma/delta T cells have a large TCR repertoire
false, it is limited bc they primarily recognize non-protein antigenic determinants
What type of selction do gamma/delta T cells undergo? where do they mature?
T cells do not undergo conventional thymic selection and development; they mature extrathymically
What are co-receptors for the TCR that facilitate the interaction of TCR with the MHC complex on the antigen-presenting cell?
CD4 and CD8
Why is protein tyrosine kinase necessary for T cells?
- *cytoplasmic tails** of CD4 and CD8 associate with a protein tyrosine kinase which
- *enhances TCR-induced activation** of the T cell upon interaction with an APC
What type of T cell contains CD4?
CD4 is present on helper T cells.
Describe the structure and what CD4 binds to
CD4 is a single-chain protein that has an extended structure.
CD4 binds (weakly) to MHC class II molecules on the surface of antigen-presenting cells
What is the function of CD4 helper Tcells?
- produce cytokines
- provide help to B cells
- stimulate cells of the innate immune system to increase their activity
CD8 is present on what type of T cell?
CTL
Describe the structure of CD8 and what it binds to
heterodimer formed by an and a chain that
are connected by a disulfide bond
binds (weakly) to MHC class I molecules on the surface of APCs or target cells
T/F ALL nucleated cells express MHC I
true
What is the function of CD8 T cells?
In addition to TCR, what other surface proteins are expressed by T cells?
- CD3
- accessory molecules (CD45, CD28/CTLA-4, CD5, Fas ligand)
- adhesion molecules (LFA-1, CD2, VLA-4, VLA-5)
- lymphokine receptors
Where is CD3 expressed and what is its function?
the CD3 complex is expressed on all T cells
serves as the signal transduction unit for the TCR
What composes the CD3 complex wrt to chains?
- 1 CD3 gamma chain,
- one CD3 delta chain,
- 2 CD3 epsilon chains
- 1 zeta homodimer
Describe the relationship of tyrosine protein kinase wrt to CD3
tyrosine protein kinases associate with the CD3 complex when antigen is bound to the TCR
enzymes promote cascade of protein phosphorylation and other events leading to activation of the T cell
Accessory molecules on T cells interact with proteins on antigen-presenting cells and/or target cells leading to either of which 3 functions?
1) activation of the T cell,
2) tighter interaction between the T cell and the APC
3) killing of a target cell
What is a (common leukocyte antigen) – a transmembrane protein tyrosine phosphatase that is involved in T cell activation? What form of the accessory moleculeis found on naive T cells? memory T cells?
CD45
CD45RA is found on naïve T cells,
CDR5RO is found on memory T cells
What is the role of the accessory molecule CD28/CTLA-4?
binds to the B7 molecule on antigen-processing cells
The CD28/CTLA-4 binding to B7 on the APC has what main role? Is it required?
delivers a costimulation signal to the T cell;
this signal (in combination with signaling through the TCR) is required for T cell activation
What is present on all T cells? when it binds its ligand on B cells, what occurs?
CD5
What is the role of the accessory T cell molecule Fas ligand?
- binds to Fas that is expressed on a target cell
- participates in initiation of apoptosis of the target cell
What is the primary function of adhesion molecules wrt T cells?
strengthen the interaction between a T cell and antigen presenting cells or target cells;
may also promote activation
What is the role of the adhesion molecule lymphocyte function antigen (LFA-1)?
interacts with the intracellular adhesion molecules
(ICAM-1, ICAM-2, and ICAM-3) on target cells
What is the role of the adhesion molecule CD2?
binds to LFA-3 on target cells and promotes cell-to-cell adhesion and T cell activation
What is the role of the adhesion molecule very late antigens (VLA-4, VLA-5)? Give when it is expressed
bind to fibronectin on target cells to enhance the interaction between the T cell and the target cell (promotes peptide sampling via the TCR)
expressed on activated cells later in the response;
Why do T cells express many lymphokine receptors?
so that they can respond to the lymphokines produced by other cells that help to regulate T cell functions
What is the role of lymphokine receptors?
Describe the lobes of the thymus gland
encapsulated and bi-lobed
each lobe is separated into distinct lobules by trabeculae connected to a sinus beneath the capsule
Each lobule of the thymus is separated into what?
a cortex and medulla
Describe what is found in the cortex
- is very densely packed with thymocytes
- network of epithelial cells called cortical epithelial cells
T/F cortical epithelial cells in the thymus express both MHC I and MHC II antigens
true
T/F there are many macrophages but few bone marrow derived dendritic cells in the cortex
false, there are very few macrophages and bone marrow derived dendritic cells in the cortex
What is the medulla populated with?
- medullary epithelial cells,
- dendritic cells (antigen-presenting cells),
- macrophages
Of the cells within the medulla, which expresses MHC I? MHC II?
both express class II and class I MHC antigens
T/F the human thymus is fully developed at birth
true
the thymic cortex contains what cells?
only immature T cells (thymocytes)
scattered macrophages
the rate of T cell production in the thymus is greatest when? What happens after?
before puberty;
after puberty, thymus begins to shrink
once T cell repertoire has formed, what is required to maintain T cell mediated immunity?
T/F shrinkage of the thymus is reversible
give reason
True
patient receives a bone marrow transplant following irradiation, the thymus is restored to its full size and activity until the patient’s new T cell repertoire is fully formed
Describe the maturation process of pre-T cells to functional T cells
- pre-T cells from bone marrow enter cortex, => massive proliferation of T cell precursors (thymocytes) occurs
- positively selected thymocytes migrate from cortex to medulla to mature and become functional T cells
T cell development in the thymus includes what?
Define positive selection. Where it occurs and what happens to those who are not selected?
positive selection for T cells with TCR that can bind to self-MHC occurs in the cortex;
non- binders undergo apoptosis
Define negative selection. Where does it occur?
negative selection for T cells that bind too tightly to self MHC+ self peptide occurs in the medulla
What are tingible body macrophages? name function and how recognized within culture
apoptotic thymocytes are phagocytosed by thymic macrophages
cortical thymus macrophages have distinctive staining pattern due to the chromatin material of the phagocytosed thymocytes that were not positively selected and underwent apoptosis
What will distinguish the different stages of thymocytes?
development of surface markers
***What are the most important markers for T cells?***
(know these cold wrt location, function…)
- CD4
- CD8
- TCR:CD3 complex
thymocytes entering the thymic cortex are what type of cells?
initially double negative: CD4-CD8-
shortly after entering the thymic cortex from the bone marrow, what happens to the thymocytes?
Describe an important characteristic about double positive thymocytes. What type of gene rearrangement occurs at this time?
CD4+CD8+ thymocytes are a rapidly dividing population
TCR (alpha and beta chain) gene rearrangement occurs within this rapidly dividing double positive population
Describe positive selection wrt TCR and MHC
if the TCR expressed on the developing thymocyte binds to MHC (either class I or class II), it will receive survival signals and will continue to develop (positive selection)
if the TCR has no affinity for MHC molecules, what occurs with the cell?
double positive cells (CD4+CD8+) that survive positive selection have what fate?
differentiate to CD3-TCR+ single positive T cells: CD4+ or CD8+
if the TCR binds to MHC class II, the developing thymocyte becomes what?
if the TCR binds to MHC class I, the developing thymocyte becomes what?
Where does positive selection take place?
single positive TCR+ cells migrate to the medulla. what occurs there?
they undergo negative selection
Describe negative selection wrt TCR and MHC
if the TCR binds to MHC-self peptide complexes on medullary APC too tightly, the cell is induced to undergo apoptosis (negative selection)
Why are the positive and negative selections necessary for the T cell repertoire?
T cell precursors that arrive in thymus from bone marrow have genetic potential to generate TCRs w/ specificity for all potential MHC-peptide combinations
The selection processes that occur in the thymus eliminate these non- functional and self-reactive T cells from the repertoire.
What is expressed on the T cells after entering the thymic cortex? Why is this a problem and what occurs after? What will allow the T cell to continue to develop?
• thymocytes rapidly become TCR+CD4+ CD8+ after entering the thymic cortex
possible autoimmunity so => these “double positive” thymocytes undergo positive selection to select for cells that bind to self MHC molecules
thymic epithelial cells in the cortex express what type of MHC
What will allow the T cell to continue to develop? What will cause them to stop development and what is their fate?
•• cells that bind MHC molecules are positively selected to continue development
thymocytes that are not selected undergo apoptosis and are removed by macrophages
***Why is positive selection for double positve T cells vital?***
the function of mature T cells depends on their ability to bind to either MHC class I or MHC class II molecules
if the TCR has no affinity for MHC, then no sampling of T cell receptor complexes for cognate peptide antigen will be possible
double positive cells (CD4+CD8+) that survive positive selection differentiate to what?
TCR+CD3+ single positive T cells: CD4+ or CD8+
bone marrow derived APCs in cortico-medullary junction and in medulla present what?
What are responsible for negative selection of self-reactive T cells?
thymic medullary APC (i.e. tingible body macrophages)
single positive T cells (CD4+ or CD8+ T cells) that survive the positive selection process are then subjected to negative selection. What does this process have as a result?
remove cells that bind the self antigens (peptides) bound to self MHC complexes
Negative selection occurs where?
negative selection process takes place in the thymic medulla
What is a transcription factor that causes the expression of several hundred host tissue-specific proteins by a subset of epithelial cells in the medullary region of the thymus?
autoimmune regulator enzyme (AIRE)
How does AIRE increase the efficiency of negative selection in the thymic medulla?
expression makes them available for uptake by medullary APCs.
Once taken up, they are processed and peptides derived from them are presented in context of MHC I and MHC II molecules on APCs and are presented to naïve T cells
If a patient presents with a broad-spectrum autoimmune disease, what would you expect the patient to be deficient in? What gene is affected?
- inability to increase the efficiency of negative selection in the thymic medulla
patients that lack a functional AIRE gene typically present with a broad-spectrum autoimmune disease known as autoimmune polyglandular syndrome type 1 or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)
