Lecture 29: Immune Regulation, Foreign vs Self Antigens Flashcards
what is regulation?
control of immune responses
what is tolerance?
prevention of immune responses
immune responses to foreign antigens diminish as the antigens are eliminated, leading to a return of the immune system to a resting state; how is this mediated?
mediated by self-regulation and regulation by other immune celsls
what are the 2 main ways the immune system regulates itself?
- Passive (default on) systems
2. active regulation
what are 2 passive systems of the immune system to regulate itself?
- antigen density changes
2. activation-induced cell death (AICD)
what are 3 active methods of immune self regulation
- cytokine secretion (contact independent)
- regulatory co-stimulation (contact dependent)
- induction of apoptosis or energy
what cells secrete cytokines in active regulation of the immune system/
regulatory T cells and myeloid reg cells
what are 2 examples of co-stimulation in immune regulation?
- PD-1 & PD-L1
2. CTLA4 & CD80/86
t/f as the antigen concentration decreases, so does the immune response
t
continued immune responsiveness requires continuous exposure to ____
antigens
foreign antigens promote the survival of activated antigen-reactive lymphocytes through induction of _____, an anti-apoptotic protein
Bcl-2
clearance of antigen via _______ eventually results in less antigen being available to activate B and T cells
phagocytosis of immune complexes
when Bcl-2 expression drops, this makes the activated lymphocytes more susceptible to ______
apoptosis
immune-mediated elimination of foreign antigen deprived immune effector cells of ___ signals, resulting in _____
survival signals; causes effector cells that are o longer need to die by apoptosis
memory lymphocytes are ____ and therefore survive
quiescent
a high concentration of circulating ____ complexes indicate that there is no need for further B cell activatio
antigen-IgG complexex
immune complexes formed by antigen-IgG crosslink ____ and ____ on B cells leading to the phosphorylation of ___on the cytoplasmic tail of ___
surface immunoglobulin and FcyRIIb; ITIM; FcyRIIb
negative feedback from antibodies regulates further activation of ___ cells
B
in negative feedback to regulate B cell activation, a ____ is recruited to the ITIM of B cells and blocks further signalling through the BCR
phosphatase
the BCR is assocoiated with ____ that has an ITIM on its cytoplasic tail
CD22
what happens to the ITIM on the cytoplasmic tail of CD22 when B cells are activated?
is phosphorylated and recruits SHP-1 tyrosine phosphatase
once antigen levels drop., there will be a decrease in BCR signalling, allowing ____ to remove any residual phosphatases from the ___
SHP-1; ITIMS
CD22 knockout mice are prone to ____ as they age
autoimmunity
CD___ inhibit B cell activatio
CD22
CD5 is expressed on what cell types?
T cells and B-1 subset of cells
CD5 promotes ___ of multiple signalling pathways, which can lead to secretion of ___, which downregulates immune responsiveness
activation; IL-10
what type of B cells secrete immunoregulatory IL-10 when activated?
B10 regulatory cells
sometimes a competing foreign antigen can regulate the immune response to an unrelated foreign antigen, what happens in this case?
an immuno-dominant antigen that stimulates a Th1 response with attendant IFN-y synthesis would down-regulate a less potent Th2 response to an unrelated antigen
what is an example of competition between antigens?
cytokine cross-regulation
____ is expressed after several days of T cell activation and competes with CD28 for its ligands, CD80/86
CTLA-4
CTLA-4 binding to ___ molecules deprives T cells of essential co-stimulatory signalling through CD28
B7
CTLA-4 ligation also activates a _____ that further suppresses T cells activation
phosphatase
what is the role of programmed cell death-1 (PD-1)in T cell regulation?
binds to PD-L1 and PD-L2 on APCs and inhibits T cells activation
activation-induce cell death (AICD) is an important mechanisms for maintaining ____
T cell homeostasis
T cell activation by antigen leads to expression of ___ and ___ on t cell surface
Fas and Fas ligand
what happens to the Fas and Fas ligand on T cells to cause the T cells to undergo apoptosis?
trimerization of Fas by Fas ligand on neighbouring T cells
what happens to mice that lack functional Fas or Fas lingands?
have excessive numbers of T cells ans spontaneously develop autoimmune dx
____ Treg cells that express FoxP3 develop in the periphery after continued stimulation of T cells by foreign antigen
CD4+CD25+ (aka inducible Treg cells)
CD4+CD25+ Treg cells are ___ dependent and ___ specific
IL-2, antigen
Treg cells that interact with APC via CTlA-4 induce ______ which creates an inhibitory environment
indolamine 2,3-dioxygenase (IDO)
how does idolamine 2,3-dioxygenase (IDO) create an inhibitory environment?
by converting tryptophan to kynurenine
what happens to T cells that are deprived of tryptophan?
die by apoptosis
T reg cells secrete what inhibitory cytokines>
IL-10 and TGF beta
T reg cells compete for ____
T cell growth-promoting IL-2
what is the expected effect of decreased Treg and increased T reg?
decreased Treg: limit unwanted immune repsonse (ex: autoimmunity, allograft rejection)
increased Treg: promote desirable immune repsonse (ex: anti-tumour)
under some conditions, macrophages produce ____ which inhibit immune responses in a non-specific manner
prostaglandins like PGE2
PGE2 produced by macrophages promotes _____ accumulation in T cells, which inhibits the synthesis and signalling of what cytokine?
cAMP; IL-2
Il-2 is needed for ____ and ____
clonal expansion and survival
what are myeloid-derived suppressor cells?
immune myeloid cells that suppress antigen-specific T cell responses
how to myeloid-derived suppressor cells suppress antigen-specific T cell responses?
by secreting IL-10, TGFB, and or IDO
myelod-derived suppressor cells can also express ____
PD-L1
what is central tolerance?
negative selection to remove developing lymphocytes with receptors that might become self reactive
what is peripheral tolerance?
deletion, induction to anergy or active regulation (i.e. by T regs ) of lymphocytes with self-reactive capacity after development
____ refers to an active state of specific immunologic unresponsiveness exhibiting antigen specificity
tolerance
tolerance may involve the elimination of _____ cells or changing them so they cannot ____-
potentially self-reactive; generate an inflammatory immune response
failure to develop and maintain tolerance to self antigens lead to ____
autoimmunity
t/f multiple sclerosis is an autoimmune dx
true
in central tolerance, lymphocytes express antigen receptors specific for a particular self antigen and they encounter that antigen during ___ and this causes ____
development; apoptosis of the lymphocyte
many self antigens found in other tissues are also expressed in the ___, so that responsive T cells are also deleted
thymus
the expression of antigens in central tolerance is controlled by what transcription factor?
AIRE
some cells with high affinity for self-antigens are intentionally kept to serve what purpose?
regulatory functions (hopefully)
the T regs that are produced by central tolerance are called ____. Are they the same as the peripheral Treg cells?
thymic T reg cells (tTreg cells)
CD4+CD25+ tTreg cells are AKA ____
natural Treg cells
CD4+CD25+ tTreg cells with high affinity for self antigen express ____ and arise in the ___
FoxP3; thymus
tTreg cells migrate to the periphery where they suppress immune responses to self antigen by secreting ______ and ____ etc.
IL-10 and TGF-B
do CD8+ tTreg cells express FoxP3?
no, but they still inhibit the developmemt of immunity to self antigens
peripheral tolerance can happen in what 3 ways?
- apoptosis
- anergy
- regulation
what 3 things are REQUIRED to activate a T cell response?
antigen presentation must be from APC, cytokines, co-stimulation of Cd28 to CD80/86
tolerance is more easily induced in ____ lymphocytes
immature
t/f fetal exposure to self antigens before the immune system is fully developed results in tolerance
t
_____ promotes and maintains tolerance
long term persistence of antigen
do high doses of antigen tend to promote tolerance or an immune response?
tolerance
antigens introduced by what routes tend to promote tolerance?
oral and IV
___(low/high) levels of costimulation lead to tolerance
low
exposure to antigen in the absence of adjuvants (ie w/o PRR stimulation) ____ (promotes/inhibits) tolerance
promotes
antigen presentation by immature or unactivated antigenpresenting cells ____ (promotes or inhibits) tolerance
promotes
certain self antigens are located in tissues w/ no lymphatic drainage (ex: lens of eye). Exposure of T cells to these autoantigens can result in ____
autoimmune dx
the absence of ____ on most cells prevents the presentation of antigen to T helper cells
MHC2
the absence of costimulation of T cells results in ____, since T cells that bind self antigen via TCR w/o costimulation can either undergo ____ or become ___
clonal anergy; apoptosis or anergic
what does it mean to be anergic?
unresponsive
t/f CTLA-4, PD-1 and AICD are all involved in marinating peripheral tolerance to self-antigen
t
