Effector responses (7)

Neutralization of pathogens and toxins

antibodies can coat viruses to prevent their entry into cells (ex HIV w/ CD4+ using glp120, flu binding to sugar-modified proteins on ep cells)

Agglutination

of bacteria forms large clumps that do not enter cells easily (enhances clearance)

opsonization

promotes phagocytosis, the antibodies bind Fc receptors at the surface of the phagocytic cells

Complement activation

will generate the membrane attack complex (MAC), some complement factors can also opsonize pathogens (C3b) to activate phagocytosis through binding to complement receptors

ADCC (antibody-dependent cell-mediated cytotoxicity)

- NK cells do not exp a TCR but exp the FcγRIII (binds IgG)

- The antibody binding triggers the release of cytotoxic molecules

- some therapies against cancers using monoclonal antibodies attempt at stimulating ...

Degranulation

- Granulocytes exp Fc receptors: the binding of the antibody initiates the release of granules contents

- used against parasitic worms

Antibodies

- belong to different classes and mediate different functions

- bind to different types of Fc receptors

IgM

- good at activating COMPLEMENT (multiple Fc) and at agglutinating pathogens (pentavalent molecule = 10 binding sites)

IgG

- 4 classes in humans: IgG1, IgG2, IG3, Ig4

- All classes enhance phagocytosis

IgG1

ADCC

IgG1, IgG3

complement activation

IgA

- Major antibodies found as multimers in secretions (mucus, tears, saliva, milk) = can neutralize toxins

- Monomers in the blood = activate ADCC, phagocytosis, degranulation

- They DO NOT fix complement

IgE

- Involved in allergies, asthma

- used to fight against parasitic worms

IgD

- Minor presence in the blood

- higher levels in secretions

Fc receptors (FcRs)

- bind the Fc moiety of the antibodies

- each binds a particular class of Ig

humoral, cellular

Fc receptors constitute a physical bridge between ____ and ______ responses

multiple immune complexes

The cross linking of ______ ____ ____ can intiate the Fc receptor signaling (not one antibody alone)

ITAM, ITIM

Most Fc receptors require a γ chain to provide an ______ motif (inhibitory signal: _____)

Poly-Ig R

transport of IgA and IgM across epithelia

FcRn (neonatal)

- related to MHC I (associates with β2-microglobulin)

- Transfers Ig from mother to developing fetus

FcR on macrophages

activates cytokine expression (IL-1, IL-6, TNF) and enhances phagocytosis

FcγRIIb

- Inhibitory receptor on B cells instructs the B cells that enough antibodies are present in the blood stream

- Maintains the dendritic cells inactive at low concentrations of antibodies (the cells will need ACTIVATION of PRRs to overcome the negative signals)

FcεR

- expressed on mast cells & eosinophils

- will trigger DEGRANULATION of the cells when binding IgE

1. Helper T cell-mediated (CD4+)

2. Cytotoxic T cell-mediated (CD8+)

3. Innate-like cytotoxic responses (NK and NKT cells)

3 categories of cell-mediated effector responses

cell-mediated immunity

involves T cells and cytotoxic lymphocytes that act DIRECTLY on infected or abnormal cells (instead of using antibodies)

Th CD4+ cells

differentiate into multiple subsets, secrete various cytokines

Cytotoxic effector cells

- CD8+ CTLs / CD4+ NKT, NK cells (innate)

- induces APOPTOSIS of the target cells

Cytotoxic T lymphocytes (CTLs)

T cells that kill infected, cancerous cells or damaged host cells

TCR, MHC I, co-stimulatory signal, IL-2

CTL Activation requires 3 signals:

1. ____ recognizes a peptide presented on a ______ by a "liscensed" dendritic cell

2. _________ (CD28-CD80/86)

3. signal from _____ (cytokine up-regulated following the first 2 signals)

CTL-P

CTL precursor (naïve CD8+)

Licensed APC

usually a dendritic cell

CD4+ Helper T cell (TH)

coordinate and enhance immune responses:

- Activate macrophages and APCs

- provide help signals (via cytokines and CD40L) that allow dendritic cells to "license" CD8+ T cell activation

- Shape immune responses through different Th subsets

Licensing

allows cross-presentation = extracellular antigens (from viruses or tumor cells) can be internalized and presented on MHC I

TH1 CD4+, PRRs

Licensing is accomplished through the help of ______ or activation of _____

granules content, Fas/ FaL

Killing of cells by CTLs

1. release of ____ (granzyme, perforin)

2. interaction ___/___ (TNF family)

Interaction CTL-target cell

very similar to interaction T cell-APC

LFA-1, CTL, ICAM-1

TCR signaling changes the activation state of ____ on the _____ : the interaction between LFA-1 and ______ promotes a tight interaction between the two cells

Perforin

can insert into the membrane of the target cell and create pores (sequence homology to complement C9)

Granzyme

- a serine protease

- activates apoptosis inside target cell leading to DNA fragmentation (viral DNA can also get fragmented)

CTL activation

Perforin and granzyme B get-upregulated following _____ ____

Natural Killer (NK) cells

- 5-10% of circulating lymphocytes

- belong to innate lymphoid cells (ILK)

- DO NOT DEV IN THE THYMUS

- lack antigen specific receptors and play a major role in the targeting of infected cells, tumor cells and stressed cells

innate immune cytokines

NK cells get activated BEFORE CTLs by ____ ____ ___ (IFN-α, IFN-β, IL-12)

macrophage phagocytosis, TH1 differentiation

NK cells secrete IFN-γ to stimulate ____ ____ and _____ ____

NK receptors (NKRs)

NK cells express ______, either activatory or inhibitory that help them detect altered self

Missing self model

some tumor cells down-regulate MHC I to escape CD8+ cells, which activates NK cells

Balanced signals model

- target cells are not necessarily MHC I-

- the balance between NEGATIVE and POSITIVE SIGNALS affects the activation of the NK cells

Inhibitory NK receptors

- Bind MHC I, block the NK cell from killing

- ITIM motifs

Activating receptors

- Trigger NK-cell cytotoxicity if not overridden by inhibitory signals

- Bind MHC I ligands activated by stress, MHC-I-like molecules from viruses

- ITAM motifs

NKT cells

- express an invariant TCR that recognizes glycolipid antigens presented by CDI (non-classical MHC I)

- involved in immunity against low-dose bacterial infections, tumors and viruses

helper and cytotoxic

NKT cells can act as both ____ ____ _____ cells (CD4+ or CD4+)

Fas/ FasL

NKT cell killing mostly through ____/___ interactions

weak

The binding of the TCR to the MHC is ___ and not easy to detect

MHC tetramers

development of ____ = the bindings between several TCRs and MHC-peptide complexes stabilizes the interaction

peptide

the tetramers allow for the tracking of ____ -specific T cells