MCDB 436 (9): T-cell Mediated Immunity

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

1) stromal cells + HEVs secrete CCL21
2) DCs have CCR7 to bind CCL21, migrate into developing lymph node
3) DCs secrete CCL19, attracting T cells with CCR7 to developing lymph node
4) B cells initially attracted by CCL19 also with CCR7
5) 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

1) circulating lymphocyte enters HEV
2) L-selectin to GlyCAM-1 + CD34 + sLeX, allowing rolling interaction
3) LFA-1 activated by CCR7 signaling in response to CCL21 bound
4) activated LFA-1 binds to ICAM-1
5) 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