Mechanisms of Tolerance Flashcards
what is immunogenic tolerance?
permits immune attack on non-self and tolerance of self-Ag
1st step of central tolerance of B cells
B cell develops BCR in bone marrow via random selection of V,D, J regions
what is negative selection?
removal of self reactive B cells
which cells undergo negative selection?
BCR+ B cells aka immature B cell (with IgM)
how are self-Ag presented to B cells?
surface bound self-Ag is expressed on bone marrow stromal cells to the IgM+ B Cells OR self-Ag released from bone marrow to be soluble
what occurs to make the B cell apoptose?
strong binding to multivalent self-Ag (on bone marrow cells) with crosslinking of BCR (multiple BCRs bind to multiple spots)
what occurs to make the B cell anergic?
strong binding to soluble self-Ag without crosslinking of BCR (weaker signal)
what is anergy?
self reactive B cells (soluble selfAg) survive andenter the periphery as an anergic naive mature B cell (IgM- IgD+)
what is an anergic naive mature B cell
self reactive B cell that can produce cytokines but cannot proliferate to become a plasma cell and is UNRESPONSIVE to Ag in the periphery
what occurs to make the B cell survive?
no recognition of self Ag, and cell enters the periphery as naive mature B cell (IgM+, IgD+)
what occurs if there is strong BCR binding to multivalent or soluble self-Ag? (other than anergy or death)
persistent RAG1/2 expression
what does RAG1/2 do?
is a recombinase, rearranges L chain DNA to generate a new BCR specificity (basically it makes a new BCR and tests it again)
what if B cell does not recognize self-Ag?
native mature B cell (IgM+ IgD+)
what happens once negative selection has occurred?
mature naive CXCR5+ B cells localize to follicles following CXCL13 gradient
what gradient makes mature naive B cells localize to follicles?
CXCL13
what is B cell positive selection?
promotion of a fraction of immature B cells to become mature B cells in secondary lymphoid tissues
what is a pro T cell?
a double negative T cell with no CD4 or CD8 and no TCR) that travels from the bone marrow to the thymus
first step of differentiation into a T cell
bone marrow stem cell –> pro-T cell
what occurs once the pro-T cell is in the thymus?
Pro-T cells rearrange the beta chain gene of TCR and express the protein on the surface becoming a Pre-T cell
second step of differentiation into a T cell
pro-T cell +beta chain TCR–> pre-T cell
what is a pre-T cell?
T cell with a recombined Beta chain of TCR
what occurs if beta chain rearrangement is successful?
alpha chain is rearranged
what occurs if both alpha and beta chains are both successfully rearranged?
TCR is fully made, inducing CD4 AND CD8 (BOTH) gene expression, making a double positive T cell (CD4+CD8+)
what is a DP T cell?
double positive T cell, a pre-T cell that has successfully recombined its alpha and beta chains to make a TCR, and has BOTH CD4 AND CD8 gene expression
third step of differentiation into a T cell
pre-T cell +alpha chain (=full TCR) –>DP T cell (CD4+CD8+)
what occurs in DP T cell positive selection?
DP T cells engage cortical thymic epithelial cells (CTEC) through HLA-self-Ag-TCR
what occurs if there is strong binding of DP T cell to self-Ag on CTEC?
survival of the DP T cell
IL-7 cytokine is released as survival signal
what occurs if there is a good CD4 fit with MHC II?
DP T cell turns into T helper cell and the CD8 genes are turned off forever
what occurs if there is good CD8 fit with MHC I?
DP T cell turns into T cytotoxic cell and the CD4 genes are turned off forever
what occurs if there is weak or no binding of DP T cell to self-Ag on CTEC?
DP T cell undergoes apoptosis
(basically trying to test “will it bind to an MHC? and which one is it going to be??”
4th step of differentiation into a T cell
DP T cell–>positive selection–>SP T cell (either CD4+ or CD8+)
what is negative selection for T cells?
testing SP T cells to REMOVE self reactive cells (if recognize self Ag, are removed by macrophages) (now has CD3+)
how are self-Ag presented to SP T cells?
medullary thymic epithelial cells (MTEC) release self-Ag for thymic DC uptake and presentation (SP T cell binds through HLA-selfAg-TCR)
how do MTEC produce all self-Ag?
expression of autoimmune regulator gene (AIRE)
what substance matures the thymic DC?
Hassall’s corpuscles produce TSLP
what occurs if TCR has weak binding to Self-Ag/MHC?
it survives and becomes a CD4-CD8+CD3+ or CD4+CD8-CD3+
what occurs if there is STRONG binding to self-Ag/MHC?
apoptosis
what occurs if there is NO binding of TCR to self-Ag/MHC
apoptosis
5th step of differentiation into a T cell
SP T Cell –>negative selection–>naive mature CCR7+ T cell (with either CD4 or CD8 AND TCR/CD3!)
what occurs once the naive mature T cells are made?
CCR7 is upregulated to localize the cell to the T cell zone in the lymph node and spleen. it follows a CCL19/21 gradient to the paracortex.
what gradient do naive mature T cells follow to the periphery?
CCL19/21
is central tolerance foolproof?
no, many self reactive B and T lymphocytes enter the circulation. therefore, peripheral tolerance developed.
what status dictates the difference between tolerance and immunity?
DC maturation
what are 3 mechanisms that could provide signal 1 to immature APC?
- binding of microbial or self Ag
- microbial component (PAMP) detected by DC PRR
- innate cells produce cytokine like TNFalpha to activate DC
what causes signal 2?
microbial components and cytokines together upregulate B7 receptor (aka CD80/CD86)
what causes signal 3
microbial components and/or cytokines promote APC cytokine release (depending on signals 1+2)
what are the 3 signals for T cell activation?
signal 1: TCR binding to mature APC presenting peptide
signal 2: B7 binding to CD28
signal 3: cytokine release from mature APC bind to cytokine receptor on T cell (promotes differentiation)
what signal promotes T cell proliferation?
signals 1+2
what signal promotes T cell differentiation?
signal 3
what does release of IL-12 for signal 3 indicate?
differentiation into Th1 cell (IFNgamma)
what does release of IL-4 for signal 3 indicate?
differentiation into Th2 cell (IL-4, IL-5, IL-13)
what does release of IL-6 and TGFbeta for signal 3 indicate?
differentiation into Th17 (IL-17, IL-22, IL-21)
what does release of IL-2 and TGFbeta1 for signal 3 indicate?
differentiation into Treg cells (IL-10, TGFbeta1)
what do Th1 cells help with?
cellular immunity
clearance of intracellular pathogens
what do Th2 cells help with?
humoral immunity
clearance of certain extracellular pathogens
allergy
what do Th17 cells help with?
tissue inflammation
autoimmunity
clearance of certain extracellular pathogens
what do Treg cells help with?
tolerance/immune suppression
what are peripheral tolerance mechanisms?
processes to eliminate or limit responses of self reactive lymphocytes in lymphoid organs and tissues (after central tolerance failed)
3 mechanisms of peripheral tolerance of T cells?
- anergy
- deletion (apoptosis)
- suppression (Treg block)
how does a cell get stuck in anergy? (signal1 steady state)
via steady state self-Ag presentation - immature APC is not challenged by Ag , so it can only provide signal 1. T cell is self reactive and is binding to self peptide on immature APC, but doesn’t get any other signal. so it is inactivated as “tolerant” and considered anergic
what occurs if self-Ag is presented by mature APC (not in steady state)
all 3 signals are given and self reactive T cell is activated. could possibly cause tissue damage.
how does a cell get stuck in anergy? (not steady state)
mature APC presents self-Ag to self reactive T cell and gets all 3 signals. however, self reactive T cells have higher basal levels of CTLA-4 (due to persistence of self Ag) and CTLA-4 outcompetes CD28 binding (signal 2)
why is there a higher level of CTLA-4 on self reactive T cells?
lot of contact with self reactive T cells and mature DC/APC (persistent self Ag) makes the T cell activate very slowly
how does CTLA-4 binding outcompete CD28
CTLA4 binds to B7 and removes phosphates from signaling molecules for signal 1+3 TCR and cytokine receptors. this stops the process altogether and the cell is inactivated/in cell cycle arrest/anergic
how are self reactive T cells “deleted”
chronic/slow self-Ag presentation starts to upregulate CTLA-4 and FasL on the self reactive T cell. Activated T cell expresses Fas-FasL and this promotes activation-induced cell death (AICD).
how are self reactive T cells suppressed?
natural Treg cells
how are natural Treg cells made?
produced in thymus, and the TCR had strong binding to self-Ag. Signal 3 sends IL-2 to generate (CD25 is the receptor)
what signal is given to make natural Treg?
IL-2 binding to CD25 receptors
why are natural Treg cells so important?
help with reducing autoimmunity (IL-2 knockout mice get multiple autoimmune diseases)
how do natural Treg cells suppress T cell activation?
cell contact-dependent inhibition via CTLA-4, surface TFGbeta, and LAG-3, which are all dependent on Foxp3 expression
what are the suppressor functions of natural Tregs dependent on /
Foxp3 expression
what are natural Tregs most effective for?
suppressing activation or most all cells
can also shut down DC and revert it back to immature state, or kill it
where are induced Treg cells (iTreg) produced?
secondary lymphoid organs/tissues in response to foreign Ag or self-Ag within an immunosuppressive environment
what can induce the Foxp3 gene?
TGFbeta
how do iTregs suppress self reactive/activated cells?
cytokine dependent inhibition through IL-10, TGFbeta and others suppress activated cells
(TGFbeta stimulates Foxp3 expression in Th3 and CD8 Treg cells)
what does TGFbeta do in suppression of self reactive T cells?
stimulates Foxp3 expression in Th3 and CD8 Treg cells
how are anergic self reactive B cells controlled in the peripehery?
they get stuck in the paracortex (t cell zone) and cannot enter the follicle because they don’t have CXCR5 (CXCR5-CCR7+)
what induces apoptosis in CXCR5-CCR7+ B cells?
Anergic B cells likely to encounter self Ag in T cell zone. Activation without Th cell help induces apoptosis because no survival factors. (aka they are activated by the self Ag but there are no T cells to help B cell survive)
how can T cells trigger apoptosis in anergic B cells?
activation of T cell zone CD4 T cells results in increased FasL expression. Anergic B cells express moderate levels of Fas. Therefore, FasL+ T cells induce apoptosis of anergic B cells by Fas/FasL binding (lack of survival factors to block death receptor pathway)
what could lead to autoimmune diseases?
susceptibility genes lead to failure of self tolerance and persistence of functional self reactive lymphocytes. if environmental trigger (infection, injury) provokes activation of the self reactive lymphocytes, there will be immune responses against self tissues.
