Reg T Cells & Tolerance (1/11) Flashcards
What is the difference between affinity and avidity?
Affinty = binding strength of once receptor to one ligand
Avidity = aggregate binding strength of multiple receptors on one surface to ligands on another (“velcro” concept)
What is the significance of avidity and T cell activation?
If there is high TCR avidity, it means you need a lower antigen concentration to initiate T cell activation
We want low avidity for self: short-lived interactions between TCR and antigen so no time for T cell to proliferate
What is AIRE?
Autoimmune regulator
It’s a gene that’s highly expressed in thymic epithelium. It’s a TF that leads to expression of ectopic self proteins i.e. pancreas, retina, ovary
It’s different from traditional TF’s bc it binds transcriptionally “silent” DNA regions, awakens “silent” DNA, recruits transcriptional machinery
What is APECED?
Autoimmune poly-endocrinopathy
It’s a syndrome that’s the result of a mutation in AIRE
Autoimmune attack on multiple endocrine structures = thyroid, parathyroid, adrenals, beta islets, gonads, vitiligo, alopecia
What is the difference between central and peripheral tolerance?
Central tolerance: established during lymphocyte development (B cells in marrow, T cells in thymus)
Involves positive and negative selection
Peripheral tolerance is what happens once B and T cells are mature & go to the periphery
What happens to establish peripheral tolerance?
Successful T cell activation requires 2 signals: TCR/MHC+ antigen and the costimulation signal (CD28 on T cell + B7 on APC)
Signal 1 without signal 2 –> anergy (much less generaiton of downstream signals, even though the machinery is all there)
Low TCR-Ag/MHC avidity or low Ag abundance to self –> ignorance, which is why we don’t respond to self (example of breaking ignorance: we don’t respond to stuff inside the eye, bc it’s not normally presented, but if you have a trauma & stuff inside the eye leaks out, we get a T cell response. Note that response starts against dominant antigen like microbial ones, but if damage persists you can start to respond against self antigens)
Clonal deletion: high density of antigen of antigen & persistent TCR triggering in absence of costimulation –> apoptosis (unclear how exactly this occurs)
What is AICD?
Activation induced cell death: it’s how we shut down the response of clonally expanded effector T cells in the terminal phase of an antigen response
Occurs in response to persistent or repeated TCR triggering
Cell death is apoptotic- fas mediated (fas is upregulated after T cell activation)
Note that anti-fas or anti-fasL antibodies inhibit AICD and that fas or fasL deficiency leads to T cell overproliferation
Also inappropriate AICD –> pathological T cell loss i.e. in HIV
What is CTLA-4?
A natural brake on T cell response, expressed on activated T cells & binds CD80/86 with higher avidity than CD28, delivers inhibitory signal to responder T cell
A drug, CTLA-4-Ig = CTLA + IgG attached making it live longer in the blood. It binds costimulatory molecules with a higher affinity than the endogenous CTLA (of course, it doesn’t just turn off the pathological T cells– targets all T cells)
What is the main extrinsic mechanism that induces peripheral tolerance?
Regulatory T cells
What are Treg’s?
T cells that inhibit the proliferative and/or cytokine response to antigen. Defined functionally because all the markers on T cells are on other T cells
What are CD4+/CD25+ Treg’s?
They don’t secrete IL-2, IL-4, or IFN-gamma. They also do contact-dependent inhibition of local responder T cells
Constitutively express CTLA-4, which is associated with activated T cell that is about to shut down but it’s always present on these cells!
Depends on IL-2 for maintenance of regulatory phenotype or for survival
IL-2 deficiency and CD25- deficiency are both associated with decreased Treg numbers & autoimmunity
How do natural Treg’s develop? How do they function?
Treg career choice occurs after + and - selection in thymus, but before exit
It’s cells that are triggered by self Ag and prob would have undergone apoptosis bc were too self reactive but somehow they become reg T cells instead
FoxP3 is the TF that is decisive to become Treg’s (if no FoxP3, no CD4+/CD25+ Treg’s and autoimmunity). Note that FoxP3 like CD25 are expressed after the effector T cell
What do nTreg’s recognize?
People don’t know 100% but assume it is self antigens
TCR-V region on Treg’s and effector CD4+ are only 20% overlapping
How do induced Treg’s arise?
In the periphery
They have a slightly different phenotype than the natural Treg’s
Naive CD4+ –> CD4+CD25+FoxP3+
Occurs when you have TCR cross-linking in presence of TGF-beta in vitro or suboptimal intigen presentation in vivo
In the lamina propira, how is the balance of Treg v Th17 phenotype maintained?
In the GALT lamina propira, there are normally low levels of co-stimulation (CD80/86) and secretion of TGF-beta/retinoic acid which both decrease inflammation
Upon tissue damage/pathogen inflammation, you get increased production of IL-6 and conversion from Treg to Th17
Note that retinoic acid in the gut is important and it reduces sensitvity of naive CD4+ T cells to inflmamatory cytokines like IL-6, IFN-gamma, IL-17
