T Cells 6 Flashcards
what happens after T cell activity?
contraction and negative regulation of T cells
and restoration of epithelial activity
when does the immune response contract?
within 10-14 days of infection –> at the end of the primary immune response, once Ag is cleared
how do Treg cells help with contraction?
by releasing inhibitory cytokines
how are lymphocytes lost for clonal contraction?
via apoptosis
which types of lymphocytes remain after clonal contraction? what type of response will they be needed for?
memory cells –> for secondary response when antigen is encountered again
what are the 2 unknown aspects of clonal contraction?
- is clonal contraction triggered by a lack of Ag or an active switch?
- how are memory cells selected for survival instead of death induction
what are the 2 apoptosis pathways?
- intrinsic pathway
- extrinsic pathway
what is another name for the intrinsic apoptosis pathway? how does the intrinsic pathway work?
“death by neglect”
lack of IL2Ralpha expression = absence of IL-2 survival signal = apoptosis
what property of IL-2Ralpha allows the intrinsic pathway to occur? what type of molecules have this common property?
IL-2Ralpha has transient expression, so it is impermanent and can therefore be reduced when needed
common for all cytokine receptor expression
what are the 2 types of inhibitory/regulatory receptors?
- CTLA-4
- PD-1
what is the function of CTLA-4?
downregulates T cell activation
how does CTLA-4 downregulate T cell activation?
binds B7 molecules with higher affinity than CD28, so it sequesters B7 and prevents CD28 binding
ultimately shuts down signaling pathways
when is CTLA-4 induced?
after signal 1,2,3 about 24h after T cell activation
when does CTLA-4 activity peak?
2-3 days post-stimulation
how does CTLA-4 get expressed on cell membrane?
CTLA-4 is fully translated intracellularly but undergoes PHOSPHORYLATION (post-translational regulation)
how many B7 molecules does CD28 bind vs how many B7 molecules does CTLA-4 bind?
1 CD28 binds 1 B7
1 CTLA-4 binds 2 B7
describe what happens when effector T cell binds APC (describe without vs with CTLA-4)
WITHOUT:
- Effector T cell binds APC
- CD28 can bind B7 and allow proliferation
WITH CTLA-4:
- Effector T cell binds APC
- CTLA-4 binds B7, blocking CD28 and blocking proliferation
ultimately, how does CTLA-4 affect sensitivity of T cells to APCs and how does affect proliferation?
CTLA-4 makes activated T cells less sensitive than naive T cells to stimulation by APCs
reduces IL-2 production which reduces proliferation and prevents lymphocyte overgrowth
what happens in mice that don’t have CTLA-4?
too many lymphocytes –> disease
what cells express PD-1?
activated T cells express PD-1
What does PD-1 bind? (2)
- PDL-1
- PDL-2
what type of cells express PDL-1?
constitutively express on many cells
what type of cells express PDL-2?
on APCs during inflammation
what is the function of PD-1?
downregulates T cell activation/function
what is PD-1 a marker of? when is this common?
marker of T cell exhaustion, common in chronic diseases
why is PD-1 a marker of exhaustion?
if cell gets tired of proliferating, etc. it will “wave a white flag” aka allow PD-1 activity
what are the 2 subsets of Treg cells?
- Natural Treg (nTreg)
- Induced/adaptive Treg (iTreg)
where do nTregs come from?
produced directly in thymus and can exert its function as is
when are nTregs selected?
have high affinity for self peptides to dampen immune response to them
helps prevent autoimmunity
what 5 molecules do nTregs express?
- TCR
- CD4
- IL2Ralpha
- CTLA-4
- FoxP3 (master transcriptional regulator)
do nTregs express IL-2?
no, so they rely on other cells
where do iTregs come from?
arise in periphery from CD4+ T cells
what 5 molecules do iTregs express?
- TCR
- CD4
- IL2Ralpha
- CTLA-4
- usually FoxP3 (master transcriptional regulator)
what are the 4 steps of iTreg signaling?
- signal 3: IL-2, TGF-beta
- TF: STAT5
- master transcriptional regulator: FoxP3
- secretes IL-10, TGF-beta
what effector cytokines do both Treg cell types secrete? what type of cytokines are they?
IL-10 and TGF-beta
anti-inflammatory cytokines
how do IL-10 and TGF-beta affect immune cells? what specific type of immune cell do they mainly affect?
IL-10 and TGF-beta repress immune cells, mainly T cells
what are the 4 main functions of Tregs?
- deplete local area of stimulating cytokines
- produce immunosuppressive/anti-inflammatory cytokines
- directly kill T cells
- inhibit APC activity
how do Tregs deplete the local area of stimulating cytokines?
express IL-2Ralpha (CD25) to sequester IL-2 and prevent proliferation signal
do Tregs make their own IL-2?
no, they steal it from other cells and only express IL-2Ralpha
what anti-inflammatory cytokines do Tregs produce? what do they do?
IL-10 and TGF-beta
stop pro-inflammatory cytokines
how do Tregs directly kill T cells? (2)
- granzymes
- metabolic disruption
how do Tregs inhibit APC activity? (2)
- B7 sequestration by CTLA4
- endocytose B7 from APCs
what are 3 roles of IL-10?
- inhibits MHC expression from APCs
- inhibits B7 expression from APCs
- inhibit production of TH1 and TH17 cytokines
what are 2 roles of TGF-beta?
- inhibits T cell proliferation
- inhibits development and function of TH1 and TH2
where does nTreg arise? why?
nTreg arises in thymus –> mainly recognizes self-peptide:MHC
where does iTreg arise? why?
iTreg arises in periphery –> recognizes self-peptide/Ag peptide:MHC
