T Lymphocyte Mediated Immunity Flashcards
general principle of T-cell activation and differentiation
antigen recognition - activation - clonal expansion - differentiation - effector functions
what are high endothelial venules
specialized blood vessels that bring naive B and T cells to the lymph nodes
- found in T cell zones (paracortical area)
formation and organization of secondary lymphoid organs are controlled by…
TNF family members
characteristics of the marginal sinus
- the marginal sinus separates white and red pulp
- circulating T and B cells are first delivered here when they get to the SLO
- enriched in marginal zome B cells
- T cells migrate from the marginal sinus to T-cell zones (PALS)
- B cells migrate from marginal sinus to B-cell follicles
what is the marginal sinus
area in SLO’s where circulating B and T cells are first delivered to - seperates red and white pulp
difference between marginal zone and follicular B cells
- marginal zone B cells do not recirculate, follicular do
- marginal zone = in marginal sinus
- follicular = in B cell follicle
what are Fibroblast reticular cells
stromal cells of the spleen which produce chemokines to attract T cells from the marginal sinus
what are follicular dendritic cells
lineage of dendritic cells concentrated mainly in the follicles of SLO’s - produce the chemokine CXCL13 to attract B cells
path of the antigen from delivery to SLO to when it is recognized
antigen is delivered to SLO via arterioles - antigen is taken up by dendritic cells - dendritic cell transports antigen into T-cell zones
what are MALT
mucosa-associated lymphoid tissue
- lymph node-like structures
- the epithelium overlying them contains M cells which adapt to channel antigens and pathogens directly from the gut lumen into the underlying lymphoid tissue
- e.g. peyer’s patches
what guides naive T-cell migration into the lymph node
cell adhesion molecules
what are the chemokines which attract T cells to secondary lymphoid organs
CCL19 and CCL21
how do naive T cells migrate into secondary lymphoid organs
- circulating lymphocyte enters an HEV in the lymph node
- L-selectin on T cell binds to glyCAM-1 and CD34 on endothelial cell to allow rolling
- CCR7 responds to chemokine CCL21 or 19 on endothelial surface which activates LFA-1
- LFA-1 binds to iCAM-1
- lymphocyte moves into lymph node via diapedesis
which molecules facilitate the movement of T cells from blood vessels into lymph nodes
selectins and integrins
what molecules do selectins and integrins bind to enter HEV’s
selectins: L-selectin binds CD34 or GlyCAM-1
integrins: LFA-1 binds iCAM-1
molecules do which selectins and integrins bind to enter the endothelium of mucosal lymphoid tissue or marginal sinus of spleen
selectins: L-selectin + MAdCAM-1
integrins: LPAM-1 + MAdCAM-1
what happens if T cells are activated vs not activated by APC in the secondary lymphoid organs
activated T cell: lose ability to exit the T-cell zone and begin to proliferate there over the next several days
non-activated T cell: exits from the lymph node via the cortical sinuses within hours
why can a T-cell not leave the lymph node for a few days after they recognize a pathogen?
the T cells need a few days to differentiate from naive to an effector in the SLO’s before they exit via the cortical sinus
T cells encountering properly presented antigens in circulation is very low because of their specificity. how is this resolved?
Traffic through SLO’s takes T cells past APC which are likely presenting foreign antigen since both antigen and leukocytes collect in SLO’s
trapping and activation of antigen-specific naive T cells in lymphoid tissue
- within 48 hours of antigen delivery most antigen-specific T cells can be trapped in the lymph fluid
- local inflammation stimulates an increase in influx/decrease in efflux of lymphocytes in and out of lymph node
- this is the basis for local lymph node swelling
Egress of lymphocytes from lymphoid tissue is mediated by…
Sphingosine 1-phosphate gradient
expression of the S1P receptor
antigen not encountered = increased expression
antigen encountered = decreased expression
* controlled by CD69 levels
important proteins involved in the S1P gradient
S1P lyase: degrades S1P
CD69: internalizes S1PR1 when T cells are activated
FTY720: an immunomodulatory molecule that inhibits T-cell aggression by down-modulating expression of S1PR1 by ligand-induced internalization in the lymph node
basis of the S1P gradient
- S1P levels in lymphoid tissues are low compared to blood and lymph
- S1PR1 is present at low levels on the surface of naive T cells as high levels of S1P in blood down-regulate it
- no antigen recognition = S1PR1 expression increases
- activated T cells up-regulate CD69 which down-regulates S1PR1 expression
- activated T cells eventually reexpress S1PR1 as CD69 expression decreases
why are S1P levels in lymphoid tissues low compared to blood and lymph
S1P lyase is lymphoid tissue degrades S1P
very basic explanation of the S1P gradient mechanism
the S1P gradient is needed to direct T-cell movement in the body. S1P receptors on T cells detect the gradient which pulls them towards the blood (where gradient is higher) to guide them out of the lymph node
dendritic cells in antigen presentation to T cells in SLO’s
- located throughout the body
- results in activation of naive T cells
macrophages in antigen presentation to T cells in SLO’s
- located in lymphoid tissue, connective tissue and body cavities
- results in activation of macrophages by effector and memory T cells
B cells in antigen presentation to T cells in SLO’s
- located in lymphoid tissue and peripheral blood
- results in delivery of help to B cell by T-helper cell
antigen uptake by dendritic cells in non-lymphoid tissues and delivery to T cells in lymphoid tissues
- immature conventional dendritic cells reside in tissues and are activated by MAMP’s
- TLR signalling induces expression of CCR7 and enhances processing of antigens
- CCR7 directs migration of DC to lymph node
- activated dendritic cell in T-cell zone primes naive T cells
what is T cell priming?
the first contact that antigen-specific naive T cells have with an antigen
what are the 2 major classes of dendritic cells
conventional DCs
Plasmacytoid DCs
characteristics of conventional dendritic cells
- concerned with activation of naive T cells
- subsets cDC1 and cDC2
- most abundant in non-lymphoid tissues, but some are also lymphoid tissue resident
- high MHC
- express B7
characteristics of plasmacytoid dendritic cells
- sentinels of viral infection
- secrete large amounts of type 1 IFNs
- low MHC
- express CXCR3
what are the different routes which DCs can take up, process and present protein antigens
receptor mediated phagocytosis (CD4)
macropinocytosis (CD4)
viral infection (CD8)
cross-presentation after phagocytic or macropinocytic uptake (CD8)
transfer from incoming DC to resident DC (CD4 and CD8)
cell adhesion molecule pairs in T-cell:DC interactions
LFA:1 + iCAM-1
CD2 + CD58
LFA-1 + iCAM-2
how specific antigen recognitions stabilizes T-cell:DC interactions
- T-cells initially bind APC through low affinity LFA:iCAM-1 interactions
- binding of TCRs signals LFA-1 to undergo conformational change
- this increases affinity and avidity that results in prolonged cell-cell contact
3 kinds of signals involved in activation of naive T cells by APCs
- TCR recognition of antigen peptide:MHC on surface of activated cDC’s
- co-recognition of costimulatory molecules (CD28-B7)
- cytokines delivered to activated naive T cell by APC
initial T-cell response to antigen results in…
rapid clonal expansion that is followed by clonal contraction as the immune response wanes
what is clonal contraction
activated T-cells undergo apoptosis so the immune response does not go out of control
clonal expansion of T cells is driven by…
IL-2
high-affinity IL-2 receptors are three-chain structures present on…
only activated T-cells
after a naive T-cell moves to an SLO, they are activated and express a high-affinity IL-2 receptor. what are the paracrine and autocrine functions of this?
paracrine: binding of IL-2 to its receptor promotes enhanced proliferation and can modulate T-cell differentiation
autocrine: activated T cell makes IL-2 which binds to its own high-affinity receptor and causes clonal expansion
what are the effects of additional co-stimulatory and inhibitory receptors (CTLA-4) which help control clonal expansion after T-cell activation
- CTLA-4 binds two B7, has higher affinity and outcompetes CD28 binding
- CTLA-4 can be internalized with bound B7, removing B7 from the APC surface
- CTLA-4 may transmit a negative signal that inhibits T-cell receptor signalling
what are the 3 subsets that naive T cells differentiate into
cytotoxic T cells: kill infected cells
helper T cells
regulatory T cells: stop the adaptive immune response
expression of cell-surface molecules in naive T cells
L-selectin = YES
CCR7 = YES
LFA-1 = moderate
S1PR1 = moderate
VLA-4 = NO
expression of cell-surface molecules in effector T cells
L-selectin = NO
CCR7 = NO
LFA-1 = YES
S1PR1 = NO
VLA-4 = moderate
what are the 4 subsets of helper T cells
TH1
TH2
TH17
T-FH
what are the sources of antigens targeted for the different subsets of T cells
TH1 = extracellular bacteria, microbes that resist macrophage killing
TH2 = helminth parasites
TH17 = extracellular bacteria, fungi
T-FH = nearly all microbes
what proteins are found in granules of cytotoxic T cells
perforin: delivers contents of granules into the cytoplasm of target cell
granzymes: serine proteases which activate apoptosis
granulysin: antimicrobial actions which can induce apoptosis
what does MHC I present in healthy vs infected cells
healthy = presents self-peptides
infected = presents antigens (foreign)
how T-cell mediated cytotoxicity directly kills the cell
- CTL recognizes and binds virus-infected cell
- CTL programs target for death, inducing DNA fragmentation
- CTL migrates to new target
- target cells die by apoptosis, neighbouring uninfected cell is not killed
how the extrinsic pathway for apoptosis of target cells by T cells starts
- triggered when FasL binds to Fas
- clustering of death domains in Fas recruits FADD
- FADD activate pro-caspase 8 which activates pro-caspase 3
how the intrinsic pathway for apoptosis of target cells by T cells starts
- when a cell is infected the mitochondria releases cytochrome c
- cytochrome c binds to Apaf-1
this complex assembles into an apoptosome which activates pro-caspase 9, which activates pro-caspase 3
where the intrinsic and extrinsic pathways of apoptosis by T cells converge
the activation of procaspase 3
what is the role of pro-caspase 3
enters the nucleus and cleaves DNA = cell death
what is the difference between white pulp and red pulp in SLO’s
white pulp: contains B cells, T cells, and APCs - where the immune cells interact with antigens
red pulp: contains macrophages and RBCs - found outside the white pulp and filters + recycles blood cells
