MIMM 214- T cells

Cd40 ligand and Fas ligand

• expressed on surface of effector T cells

• crucial for effector T cell function

• TM ligand, part of TNF family

fas ligand

• expressed on the surface of effector CD8+ cells and TH1 cells

• used by CD8+ cells to exert cytotoxic effect

• binds Fas on the surface of infected cells in the periphery

CD40 ligand

• expressed by Th1, TH2, TH17 and TFH cells

• binds CD40 on B cells and innate immune cells

• activate target cells

• allows for DC licensing and expression of more co stimulatory molecules

signal 1

TCR binds peptide presented by APC on MHC class I

signal 2

costimulatory signal transmitted by CD28-B7(CD80/86)

• interaction between T cell and APC

signal 3

provided mainly by IL-2 and other cytokines to some extent (IL12) inducing proliferation and differentiation into CTL

CD8+ specific consideration

• CD8+ require more co stimulation

• IL-2 can be autocrine or paracrine from a Th1 or Th 17 cell

• requires the help of effector CD4+ T cells

paracrine IL-2

comes from TH1 or TH 17

simple CD8+ activation (rare)

activated by DCs that have high co-stimulatory activity (some viral infection where DCs become infected themselves and sufficiently activated)

Majority of CD8+ activation

additional help from CD4 effector T cells and license dendritic cells to cross present

sequential CD8 + activation

• APC becomes further licensed following interaction with a CD4+ cell

• interacts with CD8+ cell independently

• key part of licensing is CD40 to APC

• IL-2 produced by CD8+ alone induces proliferation

simultaneous CD8+ activation

APC interacts with both CD4+ and CD8+ T cell at the same time

• CD40 signaling due to interaction with CD40L on CD4+ T cell

• Il-2 is secreted by both Cd8+ and CD4+ to induce proliferation of CD8+

CD40 signaling

leads to DC licensing and expression of more costimulatory molecules

activation of CD4+ cell

• Il-2 secretion

• CD40L expression

APC is licensed by activated CD4+ cells through CD40 binding

• presenting exogenous ag via MHC II

• cross presentation to present antigen via MHC I

• increased expression of CD80/86

• induction of additional molecule that activates CD8+ T cells , 41BBL and CD70 - additional costimulatory molecules

• increased IL-12

4-1BBL

• costimulatory molecule

• bind to 4-1BB

CD70

• binds to CD27

• co stimulatory molecule

MHC class I

expressed by all nucleated cells

CTL induce apoptosis by

• FAs-FasL interactions

• cytotoxic granules

Fas-FasL mediated killing

• effector CTL expresses FasL

• infected cell express Fas

• signaling cascade involves cleavage and activation of caspases → apoptosis and cell death

granule mediated killing

• CTL makes first contact to target cell via non specific adhesion

• specific recognition via TCR: pMHC

• reorganization of cytoskeleton and cytoplasmic contents (granules stained in red, microtubules in green)

• granules released at point of cell contact

granules of CTLs contain(cytotoxins)

• perforin

• granzymes (B)

perforin

aids in delivering contents of granules into the cytoplasm of target cell

granzymes , esp granzyme B

serine proteases, activate apoptosis once in the cytoplasm of target cell

granzyme/perforin mediated cytolysis

• when stimulated, CTLs release granule contents

• perforin is a pore-forming protein'; granzymes are serin protease

• perforin punches holes in the membranes and granzyme enters to induce apoptosis

caspase 3

• both FAS/FASL pathway and granule activate it

• leads to apoptosis

which mechanism does CTL use?

• perforin/granzyme is fast acting and the CTLs primary use this

• FAs-FAsL is known as a slow acting mechanism

• both can act simultaneously, so killing is more effective

response to viral infection cells

• Type I IFN

• NK cells

• Virus specific CTLs

Type I IFN (alpha/beta)

important anti-viral cytokines , can inhibit or slow viral replication

NK cells and viral response

recognize and kill infected cells and tumor cells by their absence of MHC class I

IFNgamma

• secreted by CTLs

• Type II IFN

• increase MHC class I expression in neighboring cells

• activates macrophages and stimulates production of chemokines that can recruit additional macrophages and CD8+ cells to sites of infection

Type II IFN

play a role in immune response against intracellular pathogens, secreted by T cells

TH1 responses

often involved in the response to infections by viruses and intracellular pathogens

TH2 responses

often involved in the response to parasites and other extracellular pathogens, allergies

TH 17 responses

involved in the response to infection - extracellular bacteria and fungi + autoimmunity

TFH response

involve activating B cells in the lymph node

TH1 molecules

• IFN gamma

• CD40 ligand

• Fas ligand

TH2 molecules

• IL-4

• IL-5

• IL-13

• CD40 ligand

TH 17 molecules

• IL-17

• IL-22

• CD40 ligand

Treg cells molecules

• Il-10

• TGF- beta

cross regulation

• will have a combination of different cells but one will dominate ‘

• the two patterns cross regulate each other

• these effector cytokines help reinforce the predominant subtype they are part of

IL-4 inhibits

TH1 differentiation

IFn gamma inhibits

TH2 proliferation

IL4 and ILF gamma inhibit

TH 17 differentiation

TH1/TH2 cross regulation

• master TFs commit T cells to one subset or the other

• T-bet suppresses TH2 pathway gene expression

• GATA3 suppresses TH1 pathway gene expression

decision point - Th17/Treg

• TGF beta needed for differentiation of both subsets

• IL-6 induces Th17

• normal state could favor Treg, inflammation Th17

• balance between the two is ideal

TGF beta

needed for differentiation of both Th 17 and Treg subsets

TH1 signal 3

• polarizing cytokines

• IFN-gamma and IL-12

IFN gamma

effector cytokine of TH1

T-bet

master Transcription regulator of TH 1

TH1 role

• macrophage activation

• activation and differentiation of naive cytotoxic T cell precursors into effector CTL

Th1 response

intracellular pathogens

• bacteria

• pathogens

• viruses

TH1 functions

• secretes IFN gamma at point of interaction

• targets macrophages - recognizes pMHC II on macrophage surfaces

• aid in killing microorganisms that persist in macrophage vesicles

ITP

autoimmune disorder in which the body’s immune system destroys healthy platelets , leaving patient for spontaneous bleeding and bruising

pathogens persist in macrophages

• inhibit fusion of phagosome and lysosome

• prevent acidification → lysosomal proteases can’t activate

TH1 macrophage role

• recognize pMHC II on surface

• uses CD40L to bind CD40

• secretes IFN gamma

• boosts macrophage antimicrobial activity and production of TNFalpha from the macrophage

M1 macrophages

function induced in the context of TH1 and have a boost to their antimicrobial mechanisms

M1 macrophage cytokines

• CD40L

• TNF alpha

• IFN gamma

M1 and TNFalpha

secreted TNFalpha sends survival signals to the macrophage in an autocrine fashion

CD40L and M1

CD40L binding activates macrophages and increases expression of IL-12

TH1 macrophage killing

• chronically infected macrophages

• recognize pMHC II on infected macrophages

• FasL binds Fas and triggers apoptosis of infected macrophage

LT-beta

lymphotoxin beta, produced by TH1 , is a tumor necrosis factor TNF-C , helps killing tumors or infected cells

TH1 and CD8+

• can secrete IL-2 and stimulate CD8+ cells proliferation and differentiation

• would happen in the lymph nodes

TH1 and monocyte differentiation

• in bone marrow

• secrete Il-3 and GM-CSF , which circulate in blood and act in the bone marrow = endocrine mechanisms

GM-CSF

granulocyte macrophage colony stimulating factor

Th1 and adhesion molecules

• produce TNF-alpha and LT-alpha which act on local blood vessels

• that changes expression of adhesion molecuoles on neighboring endothelium to recruit more macrophages

Th1 and chemotaxis

secrete chemokine CCL2 that attracts macrophages to the site of infection

M tuberculosis

• infects macrophages in the lungs

• often resistant to anti-microbial effects of macrophages→ leads to chornic infection, and agranuloma formation

granulomas and M. tuberculosis

• core of infected macrophages

• surrounded by layer of activated macrophages, then a layer of TH1 cells

• center becomes necrotic- cells die in the center from a combination of lack of oxygen and cytotoxic effect of activated macrophages

T-bet

master transcriptional regulator of Th1 cells

Il-4

signal 3 of TH2 cell activation

GATA-3

master trancriptional regulator of TH2

effector cytokines of TH2

• IL4

• IL-5

• IL-13

allergies/ asthma

caused by dysregulated TH2 responses

TH2 main role

clearing helminth infections

• activate eosinophils

• mast cells activation

• basophil and macrophage recruitment

STAT6

Transcription factor ,positive regulator of GATA-3 - TH2 cells

parasitic helminths

TH2 response to helminth

• can sometimes clear the pathogen (or not → chornic infection)

• reduce worm burden “weep and weep”

• facilitate tissue repair

• IgE antibodies - important for immune response against helminth

TH2 “sweep and weep”

• IL-13 can increase mucus production by goblet cells and increase turnover of epithelial tissue → mucus prevents adherence and accelerates loss of parasites

• can also stimulate smooth muscle cells to contract → leads to worm expulsion

TH2 and M2 macrophages

• IL-4 and IL-13 important for M2 activation

M2 macrophages

• alternatively activated macrophages

• aid in tissue repair and participate in worm killing and expulsion

• can form granulomas to entrap worms

• can also release toxic mediators directly onto the worm by antoibody dependant cell mediated cytotoxicity

ADCC

the killing of antibody coated target cells by cells with Fc receptors

most ADCC is mediated by NK cells

TH2 and eosinophils activation

• IL-5 activates, recruits and enhances eosinophil differentiation

• eosinophil granules contain major basic proteins MBP, which can kill parasites

• IL-13 and IL-4 lead to IgE generation, eosinophils Fc receptors recognize the igE on pathogen and can degranulate to kill it

TH2 and mast cell activation

• IL3 and IL 9 recruits mast cells

• mast cell granules contain histamines and other molecules

• increase vascular permeability

• increase intestinal motility

• increase recruitment of inflammatory molecules

• mast cells can also recognize IgE bound to pathogens

basophils

can secrete IL-4 and IL-13

can activate gobvelet cells , allow vasodilation , bind to IgE and release histmaine

Type 2 response and allergy

• allergens can enter the host via mucosal tissue and induce TH2 response. Il-4 and IL-13 induce IgE generation

• allergies are initiated by an interaction between an IgE antibody and an antigen

• IgE bind to mast cells or basophils and induce degranulation - granules contain histamines, proteases and chemokines - which will act on surrounding tissues and cause symptoms

normal IgE levels

• free circulating IgE is usually very low in concentrtion in blood serum

• healthy individuals make IgE only in response to parasitic infections

signal 3 Th17

• TGF-beta IL-6 IL-23

TH17 effector cytokines

• IL-17 Il-22

RORgamma T

TH17 master transcriptional regulator

• secretes Il-17 and Il-22

T_h17 main role

• enhances neutrophil responses and mucosal immunity

• helps respond to extracellular bacteria and fungi

• pro-inflammatory response and involved in many autoimmune disorders

type 3 response

TH17 responses to infection

TH17 and G-CSF

• IL-17 acts on stromal and myeloid cells

• these cells secrete G-CSF

• G-CSF enterscirculstion and targets bone marrow precursor to differentiste into neutrophils

CCL20

• produced by Th17

• chemoattractant for other TH17 cells to site of infection

IL-17 for psoriasis

• psoriasis is an autimmune disease that causes scaly red and white patches on the skin

IL-17 targeted using monoclonal antibodies

monoclonal antibody

antibodies produces by a single clone of B lymphocytes b, sop they are identicalk - bind specificntarget to either activate or inhibt its activity

two approches to targeting IL-17 in psiorasis using antibodies

• IL-17 receptor antagonist (blocks signaling from the IL-17 receptor)

• anti IL-17 neutralizing antibodies (binds to IL_17 and orecents it from interacting with receptor)

ILCs

activated by cytokines and different group target different pathogens

ILC2 and TH2

• produce a trio of cytokines , IL_4 and IL% and IL-13

• they generate IgE and degranulation of grnulocytes and other functions that can kill and clear helminth infection

ILC3 and TH17b

produce IL-17 to defend against bacterial infection