Lecture 7 - T cell tolerance

Question 1

How did the neonatal skin graft experiment show that tolerance is learned?

Answer 1

The neonatal mouse accepted the allograft because it was ‘taught’ that the alloantigens from the Y strain were self

Question 2

What is central tolerance?

Answer 2

Tolerogenic events that occur in central (primary) lymphoid tissues (in thymus and bone marrow. The elimination of self reactive lymphocytes during their development.

Question 3

What is peripheral tolerance?

Answer 3

Tolerogenic events that occur in peripheral lymphoid tissues. The suppression of immune responses by cells that are self recative and somehow escaped deletion during development.

Question 4

What are the three consequences of tolerogenic events?

Answer 4

Clonal deletion. Clonal anergy. Receptor editing

Question 5

What is clonal deletion?

Answer 5

Self-reactive lymphocytes are induced to die.

Question 6

What is clonal anergy?

Answer 6

Self-reactive cells are rendered non-functonal, silent or anergic

Question 7

What is receptor editing?

Answer 7

Self-reactive cells are induced to undergo additional VDJ rearrangements which results in new specificity

Question 8

How was the mechanism underlying central tolerance elucidated?

Answer 8

Made a transgenic mouse with Ig H and L genes from a single B cell clone that made anti-HEL and then mated it with another transgenic mouse for HEL (so that in the F1 mouse HEL is self) saw that most of the HEL specific B cells died via clonal deletion

Question 9

What was the conclusion of the anti-HEL monoclonal experiment?

Answer 9

Most (though not all) self-reactive B cells fail to mature and are eliminated by clonal deletion

Question 10

What’s the process of T cell development?

Answer 10

T cell precursors migrate to the thymus from bone marrow. TCR B chains undergo rearrangement. TCRs tested to determine if the TCR beta chain is functional via formation of the pre-T cell. If the receptor is functional, the pre-T cell undergoes several rounds of proliferation while expressing both chains of TCR. If the class I thymocyte binds too strongly to self it dies, if not it becomes CD8. If the class II thymocyte binds too strongly it becomes regulatory T cell (w IL-2 exp) and if not becomes CD4

Question 11

How does AIRE transcription factor play a role in tolerance?

Answer 11

It’s expresed mainly in epithelial cells in the thymmus, drives the expression of proteins that wouldn’t otherwise be expressed in the thymus so that the T cells can develop tolerance

Question 12

What would happen in a patient lacking the AIRE tx factor?

Answer 12

They’d be predisposed to autoimmunity

Question 13

What are the three mechanisms of peripheral tolerance?

Answer 13

Lack of co-stimulation (the 2 signal model of lymphocyte activation). Regulatory (suppressive) T cells. Activation-induced cell death

Question 14

What are 2 signals involved in the 2-signal model of T cell activation/tolerance?

Answer 14

Signal 1 is T cell activation through the ligation of the TCR peptide and MHC ligand. Signal 2 is costimulation when CD28 on T cell binds with B7 on APC

Question 15

What happens if a T cell only receives signal 1?

Answer 15

Tolerance/anergy. Interpreted as a negative signal and makes it harder for the T cell to be activated subsequently

Question 16

How can soluble CTLA4 be used to block T cell activation?

Answer 16

Soluble CTLA4 fusion proteins bind to B7 with higher affinity than CD28 blocking T cell activation

Question 17

How do regulatory T cells dampen responses to self-antigens?

Answer 17

Natural T-regs develop in thymus when self antigen is recongized, induced to express Foxp3 tx factor and leave thymus where they inhibit T cell activation and self-antigen effector T cell function

Question 18

What happens with a lack of FoxP3?

Answer 18

Natural T-regs can’t block self-antigen recognizing T cells. Leads to autoimmune IPEX (immunodysregulation polyendocrinopathy, enteropathy, X linked syndrome)

Question 19

How are T cell responses terminated?

Answer 19

Inbibitory co-receptors like CTLA4 or activation induced cell death

Question 20

How does activation induced cell death work?

Answer 20

Fas/CD95 expressed on activated T cells binds to FAS ligand which causes conformational change in Fas which leads to the recruitment of capsases which digest cellular DNA leading to death

Question 21

What are two B cell related ways that autoimmunity can occur?

Answer 21

Somatic hypermutation in germinal centers of self reactive B cells. Suboptimal clonal deletion during B cell development.

Question 22

What are two ways in which microbes lead to autoimmunity?

Answer 22

If they activate APCs to epxress co-stim molecules that provide costim to self-reconizing T cells. Mirobe can also mimic self-antigen so that self-reactive T cell turns on its human.

Question 23

Particular ______ alleles predispose towards autoimmunity

Answer 23

MHC

Question 24

How can mutations in negative regulators of lymphocyte activation lead to autoimmunity?

Answer 24

If a gene that normally halts TCR or BCR signalling dysfunctional, can lead to over active T or B cells and potentially self-reactive cells e.g. Fas, phosphatatses that counteract kinases

Question 25

How do defects in Fas signalling lead to autoimmunity?

Answer 25

Impair peripheral T cell apoptosis, get expanded T cell populations -> lymphadenopathy, splenomegaly, autoimmune lymphoproliferative syndrome

Question 26

How does blocking IL-2 receptor or IL-2 receptor pathway affect T cell activation?

Answer 26

Prevents or interferes with T cell proliferation

Question 27

What happens with defects in AIRE?

Answer 27

Failed presentation of self-antigen in thymus leading to maturation of autoreactive T cells that injure tissues in periphery. Called APECED autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia