co-stimulatory molecules
T-cell: CD28
APCs: CD80/86
binding of CD28:80/86 = REQUIRED for activation of naive T cells
effects of co-stimulation/lack of on T cell
MHCII:TCR + co-stimulator = activated T cell
MHCII:TCR without co-stim = anergic
co-stim without MHCII:TCR = no effect
peripheral tolerance
T cell interacts with APC with only MHCII, no co-stim molecules
immature DCs
round, smooth surface
more phagocytic
lower levels of CD80/86
lower levels of MHC II
lower levels of cytokine secretion - IL-12, IL-10, TNFa
____ and ____ activate vascular endothelium
IL-1b :: TNFa
_____ stimulates dendritic cell migration to lymph nodes and maturation
TNFa
plasmacytoid DCs
produce abundant type I IFNs, may act as helper cells for Ag presentation by conventional dendritic cells
express TLR7&9, RLR, type I IFNs
not thought to be involved in ag-specific activation of naive T cells but rather early viral infection sentinels
conventional DCs
activated by MAMPs in peripheral tissues, where they encounter pathogens -> TLR signaling induces CCR7 expression AND enhances processing of pathogen-derived Ags
resident: highly phagocytic, macropinocytic; do not express co-stimulatory molecules
TLR signaling effect on conventional DCs
induce CCR7 (chemokine receptor)
increase processing of Ags taken up into phagosomes
CCR7 signaling
respond to CCL19 and CCL21, directing them to the draining lymphoid tissue -> CCL19 + 21 provide further maturation -> co-stimulatory CD80/86 + MHC -> conventional DCs activate naive T cells, no longer phagocytic -> express CD80 + 86, MHCI/II, adhesion molecules (LFA/ICAM)
transient adhesive interactions
between T cells and APCs (CD4/MHCII and CD8/MHCI)
LFA-1 on T cell, ICAM-1 on APC
ensures the T cell doesn't bind too strongly
immunological synapse
area of contact b/t T cell and APC; aka supramolecular activation complex (SMAC)
outer (pSCMAC) + inner (cSMAC)
provides structure for directed secretion of T cell cytokines
pSMAC vs cSMAC
pSMAC - enriched for LFA-1 and talin (cytoskeletal protein) cSMAC - higher levels of TcR, CD4/CD8, CD28, CD2, PKC-e
APC signals to naive T cells
deliver signals for clonal expansion and differentiation
for both CD4 and CD8
differentiation results in generation of effector T cells (diff from naive T)
provide cytokines that induce naive CD4 into distinct subsets also
CD28-dependent co-stimulation of activated T cells
induces expression of IL-2 and IL-2R
activated T cell has alpha chain, whereas naive T cell just has beta and gamma
IL-2 comes from T cells themselves; therefore, autocrine process
activated T cell
stimulates differentiation pathway of T cells
lymphocyte clonal expansion
progenitor -> large # of lymphoctes -> removal of self-reactive immature lymphocytes by clonal deletion (thymus for T, bone marrow for B) -> pool of mature naive lymphocytes -> proliferation + differentiation of activated specific lymphocytes form a clone of effector cells
T/F: once a T cell becomes an effector cell, encounter with its specific Ag results in immune effector functions without need for co-stim
true
APC cytokine secretion
APCs secrete cytokines that drive the differentiation of T cells into different subsets and effector functions
include APCs and innate immune cells
by environmental conditions - PRR-MAMP/DAMP binding
CTLA-4
inhibitory co-receptor signal expressed after T-cell activation
structurally similar to CD28 but not the "gas pedal"
CTLA-4 binds to CD80/86 for inhibition
MUCH higher affinity than CD28
CTLA-4 effects
decreases production of T-cell derived IL-2
results in limiting proliferative response of activated T cell
shuts down activation of T cell
effector T cell
respond to target cells without costimulation
naive T recognizes Ag on APC -> secretes and responds to IL-2 -> clonal expansion -> differentiation -> effector function
for both CD4 and CD8
high endothelial venules (HEV)
specialized post-capillary venous swellings; cuboidal endothelial cells
enable lymphocytes circulating in blood to directly enter lymph node/secondary lymphoid tissues
found in all secondary lymphoid organs (except spleen) - tonsils, PIs, pharynx, etc
express receptors to interact with leukocytes; enable naive lymphocytes to move in and out of the lymph nodes from the circulatory system
recruitment of leukocytes in the development of secondary lymphoid organs
stromal cells + HEVs secrete CCL21
DCs have CCR7 to bind CCL21, migrate into developing lymph node
DCs secrete CCL19, attracting T cells with CCR7 to developing lymph node
B cells initially attracted by CCL19 also with CCR7
B cells induce differentiation of follicular dendritic cells (FDCs), secreting CXCL13 for attracting more B cells on CXCR5
CCR7
binds CCL21/19; on B, T, and DCs
CXCR5
binds CXCL13 (from FDC); on B cells
if a T cell DOESN'T encounter its specific Ag in the lymph node...
they leave the lymph node through efferent lymphatics to return to the circulation to enter another secondary lymphoid organ
if a T cell DOES encounter its specific Ag in the lymph node...
T cells lose their ability to exit from the node and become activated to proliferate and differentiate into effector T cells
after several days: regain expression of receptors to exit node
trapping of naive T cells in lymphoid tissue
bind to DCs, activated through TcRs
sailyl-Lewis X with T- and B-lymphocytes
at rest: lack expression
upon activation: strongly express s-LeX. bind to L-selectin
L-selectin
expressed on naive T cells; binds to sulfated s-LeX moieties on vascular addressins
vascular addressins
CD34 - on HEV cells GlyCAM-1 - on HEVs MAdCAM-1 - on mucosal endothelium, guides lymphocytes to MALT
use vascular addressins to get into HEV or mucosal endothelium
lymphocyte entering lymphoid tissue - process
circulating lymphocyte enters HEV
L-selectin to GlyCAM-1 + CD34 + sLeX, allowing rolling interaction
LFA-1 activated by CCR7 signaling in response to CCL21 bound
activated LFA-1 binds to ICAM-1
extravasation (encouraged by intracellular chemokine gradient)
sphingosine 1-phosphate (S1P)
bioactive lipid; establishes a gradient between lymphoid organ and circulatory fluids. allows exit of lymphocytes from lymphoid tissue
major source = hematopoietic cells, mostly erythrocytes
establish gradient through S1P degradation (erythrocytes die, no degrading enzyme)
lymphatic sys: source = lymph endothelial cells
LPP1 and LPP3 degrade; localized enzymes to plasma membrane, function as ecto-enzymes (degrade extracellularly)
S1PR1
expressed on naive T cells, responsive to S1P gradient
no Ag recog: S1PR1 promotes movement to efferent flow
Ag recog: decrease S1PR1 expression, retained in T-cell zone
effector T cells: re-express S1PR1
CD69
T cell activation marker
inc CD69 = dec S1PR1 (activating)
dec CD69 = inc S1PR1 (effector or naive)
polarizing mileu
effect of external factors on naive CD4+ T cell differentiation
environment, infection, hygiene, nutrition, epigenetics, genetics, etc.
TH1 cells
fate-specifying cytokines: IFN-gamma, IL-12, and receive from ILC1
produce: IFN-gamma
regulate: TFH cell pathway
effect: macrophage activation, inflammation, opsonizing IgG isotypes effect onto: macrophages -> kill dead intracellular bacteria
TH2 cells
fate-specifying cytokines: IL-4, and receive from ILC2 (and IgE)
produce: IL-4, IL-5, IL-13
regulate: TFH cell pathway
effect: allergic and helminth responses effect onto: bone marrow -> eosinophil (IL-5), mast cell, basophil
(IL-13) goblet cell -> mucus
TH17 cells
fate-specifying cytokines: TGF-beta, IL-6, IL-23, and receive from ILC3
produce: IL-17, IL-22
effect: inflammation effect onto:
stromal cells -> G-CSF, chemokines -> neutrophils
epithelial cells -> AMPs -> neutrophils
IL17 = proinflammatory cytokine; cascade effect IL-22 = acts on epithelial to produce AMPs
TFH cells
fate-specifying cytokines: IL-6
produce: IL-21
effect: germinal centre help effect onto: B cell -> isotype switching, affinity maturation
induced Treg cells
fate-specifying cytokines: TGF-beta, IL-2
produce: TGF-beta, IL-10
effect: regulation, suppression of inflammatory responses
innate lymphoid cells (ILC)
cells of lymphoid lineage which lack specific Ag receptors (no TcR/Ig) and lack co-receptor complexes
migrate from bone marrow and populate lymphoid tissues + peripheral organs
fewer in # than B/T
Id2
transcription factor in the common lymphocyte progenitor (CLP) required for the development of all ILCs
group 1 ILCs
intracellular bacteria + viruses -> IL-12 -> ILC1 + NK -> IFN-gamma
for TH1
group 2 ILCs
helminths -> epithelial cells -> TSLP + IL-33 + IL-25 -> ILC2 -> IL-13, IL-4, IL-5
for TH2
group 3 ILCs
intracellular bacteria -> IL-23 -> ILC3 -> IL17, IL-22
ILC-cytokine inducing responses
MAMPs by different types of microorganisms (direct/indirect)
DAMPS
cytokine signals from other cells
environmental signals (pollutants, etc)
CD4 effector T cell help
enhance effector functions - innate, isotype switching, etc
thymic stromal lymphopoietin (TSLP)
produced in response to helminths; alarmins
cytokines primarily produced by epithelial cells that sense molecular patterns of helminths (chitin)
T/F: ILCs require priming and differentiation to acquire effector functions
false