Lecture 7 - T cell tolerance Flashcards
How did the neonatal skin graft experiment show that tolerance is learned?
The neonatal mouse accepted the allograft because it was ‘taught’ that the alloantigens from the Y strain were self
What is central tolerance?
Tolerogenic events that occur in central (primary) lymphoid tissues (in thymus and bone marrow. The elimination of self reactive lymphocytes during their development.
What is peripheral tolerance?
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.
What are the three consequences of tolerogenic events?
Clonal deletion. Clonal anergy. Receptor editing
What is clonal deletion?
Self-reactive lymphocytes are induced to die.
What is clonal anergy?
Self-reactive cells are rendered non-functonal, silent or anergic
What is receptor editing?
Self-reactive cells are induced to undergo additional VDJ rearrangements which results in new specificity
How was the mechanism underlying central tolerance elucidated?
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
What was the conclusion of the anti-HEL monoclonal experiment?
Most (though not all) self-reactive B cells fail to mature and are eliminated by clonal deletion
What’s the process of T cell development?
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
How does AIRE transcription factor play a role in tolerance?
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
What would happen in a patient lacking the AIRE tx factor?
They’d be predisposed to autoimmunity
What are the three mechanisms of peripheral tolerance?
Lack of co-stimulation (the 2 signal model of lymphocyte activation). Regulatory (suppressive) T cells. Activation-induced cell death
What are 2 signals involved in the 2-signal model of T cell activation/tolerance?
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
What happens if a T cell only receives signal 1?
Tolerance/anergy. Interpreted as a negative signal and makes it harder for the T cell to be activated subsequently
How can soluble CTLA4 be used to block T cell activation?
Soluble CTLA4 fusion proteins bind to B7 with higher affinity than CD28 blocking T cell activation
How do regulatory T cells dampen responses to self-antigens?
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
What happens with a lack of FoxP3?
Natural T-regs can’t block self-antigen recognizing T cells. Leads to autoimmune IPEX (immunodysregulation polyendocrinopathy, enteropathy, X linked syndrome)
How are T cell responses terminated?
Inbibitory co-receptors like CTLA4 or activation induced cell death
How does activation induced cell death work?
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
What are two B cell related ways that autoimmunity can occur?
Somatic hypermutation in germinal centers of self reactive B cells. Suboptimal clonal deletion during B cell development.
What are two ways in which microbes lead to autoimmunity?
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.
Particular ______ alleles predispose towards autoimmunity
MHC
How can mutations in negative regulators of lymphocyte activation lead to autoimmunity?
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
How do defects in Fas signalling lead to autoimmunity?
Impair peripheral T cell apoptosis, get expanded T cell populations -> lymphadenopathy, splenomegaly, autoimmune lymphoproliferative syndrome
How does blocking IL-2 receptor or IL-2 receptor pathway affect T cell activation?
Prevents or interferes with T cell proliferation
What happens with defects in AIRE?
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
