Explain how multiple attempts can be made to productively rearrange the alpha and beta chain TCR genes.

Alpha chain: Can sustain many attempts at a functional rearrangement (the more it goes through the process the higher probability of success)

Beta: Two attempts can be made to achieve a productive rearrangement of the beta chain locus

Explain what is meant by describing a T cell as being double-negative, double-positive, or single-positive (reference is to status of CD4 and CD8 expression).

Double negative: Do not express CD8 and CD4

Double Positive: Express both CD8 and CD4

• now express an alpha/beta TCR that needs to be evaluated for proper function

Single Positive: Only express either CD8 or CD4

Describe the general meaning of an “activation threshold” for a T cell.

Activation Threshold:

• The activation threshold is the minimum signal intensity required for the probability of activation to be above zero, and it is defined by the addition of a fixed amount (the “critical perturbation”) to the baseline activity level.

Explain what property of the T cell is being tested during the process of positive selection. Explain what happens to T cells that pass or fail the positive selection step.

Property that is being tested:

• To determine if it will be able to function with self MHC of the body
• Selects for ability of TCR to interact with self MHC
• Cells lacking the ability to interact with self MHC die by apoptosis

Pass or Fail:

• Fail: if it does not reach positive selection threshold the cell dies by apoptosis
• Pass: they enter the goldi-lock zone (between pos. And neg. selection zone) or goes to neg. selection threshold where ( die by apoptosis or reprogrammed into regulatory Tcell[Treg])

Explain what property of the T cell is being tested during the process of negative selection. Explain what happens to T cells that pass or fail the negative selection step.

Negative Selection Properties:

• To determine if it's binds too strongly to self MHC in which case it would be autoreactive
• Selects against cells containing TCRs with high affinity for selfMHC or self MHC/peptide.
• Cells displaying high affinity for self MHC or self MHC and self peptides die by apoptosis

Pass Fail Neg. Selection Step:

• If the cells produced a TCR with too low affinity for self-MHC and failed

Explain the process that leads to a double-positive T cell becoming a single-positive T cell. What causes a double-positive T cell to become either a CD4+ Th cell or a CD8+ Tc cell?

Double Positive to Single Positive Tcell:

• this process occurs after the positive selection step in the cortex of the thymus.

Cause for double positive to be either CD4+(Thcell)or CD8+ (Tccell):

*this is affinity based

Explain where natural Tregs are produced. What phenotype did these cells have before they were changed into a Treg?

This is what happens to some of the cells that fail negative selection.

Produced:

• Some autoreactive CD4+ T cells develop into regulatory T cells (Treg) instead of undergoing apoptosis in the thymus.
• cells that are generated in the thymus during the process of T cell development

Phenotype before:

• Foxp3

Extra notes:

• Treg cells play an important role in controlling autoimmune responses by other CD4+ autoreactive T cells.

*Central Tolerance

Explain AIRE.

• Role of the AIRE transcription factor in the control of autoimmunity. AIRE = autoimmune regulator
• Note: Just focus on the big picture. AIRE induces the expression of tissue-specific genes within the medullary thymic epithelial cells, the cells that present MHC/peptide to developing T cells. This helps to identify T cells with TCRs expressing high affinity to self antigens expressed by tissues outside of the thymus.

A single developing T cell passes checkpoint #1 but does not pass checkpoint #2. Which one of the following statements about this cell is false?

a.) This cell is equally likely to become a Th as it is to become a Tc.

b.) This cell successfully expressed a TCR beta chain protein.

c.) This cell expresses both CD4 and CD8 on its surface (it is double positive).

d.) This cell did express a functional Pre-T cell receptor.eThis cell will not leave the thymus.

a.) This cell is equally likely to become a Th as it is to become a Tc.

A newly developed T cell dies by apoptosis if it does not display enough affinity for any MHC/peptide being presented in the thymus (cell fails positive selection). True/False: This exact same T cell may have passed positive selection if it had developed in the thymus of a different individual.

True

You develop a strain of mouse that lacks a functional AIRE gene. True/False: This mouse would not be able to experience an autoimmune disease.

False

A protein called FOXP3 is required to produce a Treg. A strain of mouse has been developed that does not have a functional FOXP3 gene, and this mouse cannot produce Tregs. True/False: This strain of mouse is highly susceptible to microbial infections.

False