Natural Killer cells and mucosal immunity

how are NK cells activated?

type I IFNs (IFN alpha, beta), TNF, IL12 (Also activated by IFN gamma made by TH1 cells)

what are the two functions of NK cells?

to kill and secrete cytokines

what cells do NK kill?

virally infected cells and tumor cells

NK cells help to mediate...

Antibody-dependent cellular cytotoxicity (ADCC) via Fc receptor (CD16)

What do NK cells produce to activate other cells?

IFN gamma

what are the steps to Antibody Dependent cell cytotoxicity (ADCC)?

1.) IgG1,3 binds to antigen on cell's surface

2.) CD16 on NK cells recognize bound antibody

3.) Cross-linking of Fc receptors signals NK cell to kill via perforins and granzymes

4.) cell lysis

what can viruses downregulate to avoid CTL?

MHC class I expression

Viruses inhibition of class I MHC expression leads to activation of....

NK cells

what are the 2 methods through which NK cells kill?

Perforin-Granzyme and Fas-FasL

Describe NK receptor-mediated killing

uses Immunoglobulin superfamily & C-type lectin receptors and recognize self molecules (e.g., MHC class I), not foreign

what are the two types of receptors for NK cells?

Activating receptors (ITAM)

Inhibitory receptors (ITIM)

Activation of NK cells is determined by...

a balance between engagement of activating and inhibitory receptors

inhibitory signals can be overrided by

Strong activation signals (SOS signals)

a macrophage with phagocytosed microbes will secrete _______ to NK cells

IL-12

An activated NK cell will secrete __________ to a macrophage

IFN-γ

what leads to diversity in NK cells?

Germ-line encoded, alternatively spliced and/or polygenic

NK cells have ___________ expression

variegated expression

what is the major route of pathogen entry?

through mucosal organs/tissues (oral specifically)

what are the benefits of our microbiota?

Help prevent colonization of pathogens and Provide nutrients to the host (Vitamin K)

what are the functions of the mucosal immune compartment?

Preserve the intestinal barrier

prevent movement of commensals into the circulation

Tolerate beneficial Ags from food and commensals

Protect mucosal tissues from invading pathogens

what are the mucosal epithelial cells?

1. IEC: Intestinal Epithelial Cells

2. Goblet cells

3. Stem cells

4. Paneth Cells

what helps to maintain barrier function?

Tight junctions

what are paneth cells?

Specialized epithelial cells at the base of the crypt that secrete antimicrobial proteins into the lumen

how are antigens recognized in the GALT (Gut-Associated Lymphoid Tissue) through the intestinal DC?

sampling antigens in the lumen by extending dendrites through tight junction

what are M cells?

specialized epithelial cells that actively transport antigen from lumen to Peyer's Patch (PP)

what happens in the Peyers patch??

secondary lymphoid organ T cell activation and B cell affinity maturation happens there!

what is the main effector molecule of the mucosal immune system?

Dimeric secretory IgA

describe the plasma cells present in the lamina propria

75,000 in normal intestine, Secrete 3-4g IgA / day in absence of infection

how does IgA transport across the epithelial barrier?

Transcytosis:

1.) IgA binds to receptor on basolateral face of epithelial cell

2.) endocytosis

3.)transcytosis to apical face of epithelial cell

4.) Release of IgA dimer at apical face of epithelial cell

what are the functions of secretory IgA?

neutralization in the lumen, endosomes, and in the lamina propria

how do naive lymphocytes enter into peyer's patch?

through High Endothelial Venules using CCR7 mediated chemotaxis and L- selectin

what happens to the naive lymphocytes if there is no exposure in the peyers patch?

they exit through the lymph back to blood stream (re-circulation)

what happens to the naive lymphocytes if there IS an exposure in the peyers patch?

Lose CCR7 and L-selectin expression (Not yet effector cells), Exit through the lymph back to the blood stream, Imprinted by DCs to return back to mucosal tissue

how do effector cells know to return to the mucosal tissue?

they are imprinted in peyers patch (before Ag they have CCR7 and L-selectin, after Ag they have CCR9 and α4β7 integrins)

the inductive site in the mucosa is __________, while the effector site is ______________

inductive is Peyers Patch, effector is the intestinal mucosa

Endothelial cells lining mucosal blood vessels contain...

MAdCAM-1 (which binds to α4β7 integrins)

what are the important components of oral immunity?

Desquamation, Oral microbiota, Secreted IgA, Saliva, Mucus Layer, Acquired Pellicle

what is Waldeyer's ring?

A ring of lymphatic tissue formed by tonsils and adenoids at the entrance of the oropharynx