MCM 2-4 T-Cell Development Flashcards
Major site of T-cell Development
Thymus in an ordered process via several checkpoints.
Become MHC-restricted and lineage committed
____ create a multitude of T-cell Receptors
gene rearrangements
Positive and negative selection
positive selection - selects for cells that can recognize self-MHC molecules
Negative - elimates T-cells that bind to self-antigens too tightly to reduce the chance of autoimmunity
each person has a
organisms that lack a thymus are
unique, self-restricted T-cell receptor repertoire
t-cell deficient
describe the thymus
organ in the upper chest, surrounded by capsule.
it is full of lymphocytes that initially interact with thymic epithelial cells and eventually cells from bone marrow (dendrites, macrophages)
where do positive and negative selection occur?
positive selection - occurs in the cortico-medullary (cortex) area (screens for those that will recognize self and bind)
negative selection - occurs in the medulla (screens against those that bind self MHC too tightly)
the thymus is composed of what cells?
lymphocytes, cortical epithelial cells, dendritic cells, and macrophages
where do T-cells originate?
mature in thymus, but originate as precursor cells in bone marrow (Derived from hematopoetic stem cells)
once mature, leave thymus and reside in lymphoid tissue
mature t-cells are described as naiive when
they have not contacted antigen yet
uncommitted T-cell Progenitor
cell produced in bone marrow, seeds thymus to be developed into specific T-cell type
committed double negative t-cell progenitor
after uncommitted t-cell progenitor
expresses a t-cell surface antigen but has not rearranged receptor chain genes yet
committed Gamma:Delta T-cell
when a committed double - TCP arranges it gamma:Delta loci before its beta loci
OR
when a committed double + thymocyte rearranging gamma:delta loci before alpha:beta
Uncommitted double positive thymocyte
a committed double - t cell progenitor rearranging its beta loci before its gamma:Delta loci
expresses both CD4 and CD8 surface antigen
committed alpha:beta t-cell
uncommitted double POSITIVE thymocyte rearranging its alpha:beta loci before its gamma:delta
expresses both CD4 and CD8
t-cells migrate from the bone marrow to the thymus to develop. What are they called and what do they express?
uncommitted progenitors
express CD34 before entering thymus
once in thymus, begin expressing CD2 and are called Double-negative progenitors because they express neither CD4 nor CD8
if the If the γ and δ chains rearrange first
its a functional gamma:delta T-cell
if beta chain rearranges first
the cell expresses the beta chain and becomes double positive for CD4 and CD8. rearrangement at the beta locus has two attempts
what is the Pre-TCR?
if beta rearrangement is successful, the exposed beta chain is bound by the pTa (surrogate alpha chain) to signal to the cell that a successful b chain has been made (called the Pre-TCR)
when does the alpha chain rearrange?
once the pre-TCR is formed with a beta chain and surrogate alpha chain attatched
alpha chain gets many attempts as there are many Valpha regions
after beta rearrangement but before alpha rearrangement
the cell can still become delta:gamma if it rearranges its delta:gamma loci
once alpha chain successfully rearranges, it removes the delta(&) chain and prevents delta:gamma formation
the formation of the alpha:beta chian involves…
a heterodimer - of beta chain and the pTa chain forms pre-cell receptor. (preTCR)
superdimer - if the b chain has ability to create functional TCR it allows 2 molecules of the pre-TCR to form a superdimer
interaction of superdimer with CD3 signaling molecules generates signals that initiate a chain rearrangement and stops synthesis of pTa (surrogate alpha chain)
once the alpha:beta T-cell is formed, it becomes either
CD4+ or CD8+. selection occurs via binding to either MHC1 or MHC2 class cells
if the thymic epithelial cell expresses MHCI, CD8 will bind and become a CD8+ T-cell
if thymic epithelial cell expresses MHCII, CD4 will bind and become a CD4+ T-cell
Positive selection occurs here: if the TCR’s bind too weakly or not at all to the MHC + Self-peptide, they will die
Negative selection
occurs in medulla
if cells bind too strongly, AKA avidity too high, they die via apoptosis. removes cells that recognize self antigen and can cause autoimmune disease
describe what forms the unique repertoire of mature t-cells in each person
thymic selection and also selection after the fact via interactions with antigens and pathogens in daily life
what is lineage commitment
process by which committed alpha:beta T-cells differentiate into either CD4+ or CD8+ cells. Occurs in thymus when exposed to thymic epithelial cells expressing either MHC1 + self or MHC2+ self
describe how t-cell gene rearragnements can be used to generate different receptors
In much the same way as B cells generate different receptors, T cells can rearrange V, J, and D loci in the chain genes for their receptors. If the rearrangement is viable (i.e. it preserves the proper reading frame), then a new receptor is produced. Any combination of V, J, and D loci can be arranged together, allowing for a large number of possible receptors.
Understand how positive and negative selection shapes the T cell repertoire of an individual
They work in tandem to ensure that the individual’s repertoire of T cells have an appropriate affinity for self-MHC. Positive selection weeds out alpha:beta T cells that bind self-MHC too weakly, whereas negative selection weeds out alpha:beta T cells that bind self-MHC too strongly. Cells that do not pass either checkpoint die by apoptosis.
cytosolic pathogens are degraded in the ______, while intravesicular pathogens and extracellular pathogens/toxins are degraded in the
cytosol, endocytic vesicles of low pH
describe the bias that exists when recruiting thymocytes to either of the two T-cell lineages
favors a:b lineage - commitment to this lineage requires only one productive gene rearrangement. also, nonproductive b chain rearrangmenets can be rescued by further rearrangement (on other homo chromosome)
commitments to the d:gamma linease requires a minimum of 2 productive rearrangemnets
Once the alpha chain is arranged (not the “dummy alpha chain”), is it possible for the cell to still come gamma/detla?
No, part of the alpha rearrangment involves deletion of the delta chain locus. If the alpha chain successfully rearranges, then the cell is committed to becoming alpha/beta T cell.
To form a mature double positive t cell, two checkpoints must be passed…what are they?
Checkpoint 1: checks for functional beta chain on surface (pre-Tcell with “dummy alpha” subunit)
Checkpoint 2: checks for functional alpha subunit
What two “things” are selected for in positive selection?
- selects for cells that can actually bind self-MHC.
2. binding of select MHC class I or II ensures lineage committment to CD8+ or CD4+
T/F: positive selection occurs for both alpha/beta and gamma/delta cells
False…only occurs for alpha/beta
