MCM 2-4 T-Cell Development

Question 1

Major site of T-cell Development

Answer 1

Thymus in an ordered process via several checkpoints.

Become MHC-restricted and lineage committed

Question 2

____ create a multitude of T-cell Receptors

Answer 2

gene rearrangements

Question 3

Positive and negative selection

Answer 3

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

Question 4

each person has a

organisms that lack a thymus are

Answer 4

unique, self-restricted T-cell receptor repertoire

t-cell deficient

Question 5

describe the thymus

Answer 5

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)

Question 6

where do positive and negative selection occur?

Answer 6

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)

Question 7

the thymus is composed of what cells?

Answer 7

lymphocytes, cortical epithelial cells, dendritic cells, and macrophages

Question 8

where do T-cells originate?

Answer 8

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

Question 9

mature t-cells are described as naiive when

Answer 9

they have not contacted antigen yet

Question 10

uncommitted T-cell Progenitor

Answer 10

cell produced in bone marrow, seeds thymus to be developed into specific T-cell type

Question 11

committed double negative t-cell progenitor

Answer 11

after uncommitted t-cell progenitor

expresses a t-cell surface antigen but has not rearranged receptor chain genes yet

Question 12

committed Gamma:Delta T-cell

Answer 12

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

Question 13

Uncommitted double positive thymocyte

Answer 13

a committed double - t cell progenitor rearranging its beta loci before its gamma:Delta loci

expresses both CD4 and CD8 surface antigen

Question 14

committed alpha:beta t-cell

Answer 14

uncommitted double POSITIVE thymocyte rearranging its alpha:beta loci before its gamma:delta

expresses both CD4 and CD8

Question 15

t-cells migrate from the bone marrow to the thymus to develop. What are they called and what do they express?

Answer 15

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

Question 16

if the If the γ and δ chains rearrange first

Answer 16

its a functional gamma:delta T-cell

Question 17

if beta chain rearranges first

Answer 17

the cell expresses the beta chain and becomes double positive for CD4 and CD8. rearrangement at the beta locus has two attempts

Question 18

what is the Pre-TCR?

Answer 18

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)

Question 19

when does the alpha chain rearrange?

Answer 19

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

Question 20

after beta rearrangement but before alpha rearrangement

Answer 20

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

Question 21

the formation of the alpha:beta chian involves…

Answer 21

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)

Question 22

once the alpha:beta T-cell is formed, it becomes either

Answer 22

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

Question 23

Negative selection

Answer 23

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

Question 24

describe what forms the unique repertoire of mature t-cells in each person

Answer 24

thymic selection and also selection after the fact via interactions with antigens and pathogens in daily life

Question 25

what is lineage commitment

Answer 25

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

Question 26

describe how t-cell gene rearragnements can be used to generate different receptors

Answer 26

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.

Question 27

Understand how positive and negative selection shapes the T cell repertoire of an individual

Answer 27

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.

Question 28

cytosolic pathogens are degraded in the ______, while intravesicular pathogens and extracellular pathogens/toxins are degraded in the

Answer 28

cytosol, endocytic vesicles of low pH

Question 29

describe the bias that exists when recruiting thymocytes to either of the two T-cell lineages

Answer 29

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

Question 30

Once the alpha chain is arranged (not the “dummy alpha chain”), is it possible for the cell to still come gamma/detla?

Answer 30

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.

Question 31

To form a mature double positive t cell, two checkpoints must be passed…what are they?

Answer 31

Checkpoint 1: checks for functional beta chain on surface (pre-Tcell with “dummy alpha” subunit)
Checkpoint 2: checks for functional alpha subunit

Question 32

What two “things” are selected for in positive selection?

Answer 32

1. 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+

Question 33

T/F: positive selection occurs for both alpha/beta and gamma/delta cells

Answer 33

False…only occurs for alpha/beta