t cell - mediated immunity

T cell activates:

incubation of Tcell with:

soluble native AG - no Tcell response

cell-bound native AG - no T cell response

soluble degraded AG - no T cell response

cell-bound degraded AG - no t cell response

degraded AG, presented by MHC molecules - T cell response - recognize the peptides in complex with MHCI&MHCII

find them in the blood

not really to differ B& T cells, bc so small.

resting lymphocyte - large nucleus, small cytoplasm

plasma cell - ER/Golgi, lager cytoplasm. ER/Golgi are in activated cell, bc theyre doing protein synthesis -> AB & cytokines

B and T cells are morphologically identical

• resting lymphocyte doesnt do much (large nucleus, small cytoplasm)

• activated - smaller nucleus, larger cytoplasm

DCs: throughout the cortex of the draining lymph node in T cell areas

macrophages: throughout the lymph node, but mainly in the marginal sinus and medullary cords

B cells: mainly in the follicles

There are professional AG presenting cells in lymph node!

where do they get activated? -> draining lymph node

• T cells enter lymph node across high endotheial venules in the cortex ->

• t cell monitor AG presented by macrophages and DCs (Scnanning progress) - brief interaction - no specific AG recognized ->

• t cells that dont encounter specific AG leave lymph node trough lymphatics (these who not encounter the DLN)->

• t cells that encounter specific AG ->proliferate and differentiate to effector cells. happens in the Tcell area of DLN

normally t cell in the blood. whats the problem? -> how to get out of the blood of the lymph node. direct connection between blood circulation system & lymph system.

via high endophelial venules -> out of the draining lymph node.

how to get back to blood circuation -> ductus deuracicus

• DCs take up AGs in the periphery => maturation (B7 - upregulation of expression - more b7 molecules on the surface)

• naive T cell circulate continiously through secondary lymphoid organs

• B7-CD28 interaction (co-stimulation = signal 2) is necessary for the activation of naive T cells!!

• when & why does the T cell express B7AG - only when it is recognised by the dcs = maturation.

• activation of naive t cell in lymph node = development of effector cell (in the lymph node)

• activation of effector t cell at site of infection of microbe - site of infection

• cell bounded -> interacts with MHC presented peptides

• domain structure peptide binding site is formed by Va and Vß

• diversity by variation of the peptide binding site

• cytoplamsic and transmembrane region

• peptide binding site - up

• similar to an Ig Fab fragment

TCRs. ABs

components: a&ß chain heavy & light chain

signal transduction: CD3 and epsilon. Iga and Igß

Affinity for AG x1: 10^-5 - 10^-7 10^-7 - 10^-11

secreted form: no yes

class swith: no yes

affinity maturation: no yes (for MHC peptide complex)

x1: dissociation contend - the lower the number the lower the dissosiation. comparison between T cell and AB.

why is this TCR dissociation high, but not higher than the AB? -> can bind to more than one specific peptide. T cell receport must recognize more, AB has to be more specific and should never “let go”

T cell should be able to detect a variety of the cells

not same as co-stimulation

-> MHC1 just one a chain

-> MHC2 a and ß chain bind to surface

CD4 and CD8 increase the sensitivity of the TCR for peptide-MHC complexes by -100-fold.

left part - co receptor -> bind to the outside

co stimulation not equal with co receptor!

co stimulation: upregulation of B7

co receptor: binding from the outside to conserved region

after elimination of Ags by T effector cells:

=> contraction of the immune response!

clonal expansion(1 tcell that expanses)-> effector functions

-> 1. CD4 -> memory T cells (long living, what you want from vaccinatio) -> 2. CD8 -> apoptosis (Lack of survival signals (>95%)

small fraction of the Tcells stays allive - some might for decades

daugther cells - genetically clones

• each lymphocyte in the body expresses an AG receptor with a unique specificity

• there are billions of lymphocytes in the body, thus there is also a repertoire of billions of different AG receptors

• each naive lyphocyte carrying unique AG receptor is the percursor of a genetically identical CLONE of daughter cells

• basically one lymphocyte selected - then daughter cells generated -> genetically the same!

specific signal & co-stimulator (MHC2, CD4) -> activates T cell

CD28 always there

B7,1 or B7,2 - only when path recognized innative

Signal 1 -> binding from the side

Signal 2 ->Co-stimulatory signal (B7.1/B7.2).

only if signals are present on the same time -> bcell activation

-> naive T cell stimulated by virus-infected DC (bc of MHCI presentation) & CD8 heterodimer)-> T cell recognizes same AG on infected epithelia cell -> Activated T cell kills infected epithelia cells

Naive t cell recognizes self AG on epithelial cell -> AG signal alone induces anergy -> t cell is unresponsive to self AG on APC

• T cell will not be activated! its even inactivated -> protection mechanism against autoimmune action -> autoreactive T cells= recognize own peptides - alot of autoreactive immune action

• what isnt there when there is no loating ? = dieing cells dont present pamps

• What happens to the shut of T cell : anergy - ‘zombie cell’ -> swim in circulation but do not react. not apoptotic. dont recieve survival signal

• anergic - unresponsive to stimulation

• once activated - doesnt need to costimulate signal! First signal must be in costimulation

interaction with DCs - problem viral activation - detected but shut off anyways

all pathogens are transported to draining lymph node -> there are the ACTIVATED Tcells

definition - activation/recognition of the MHC receptor in absence of signal2. if only signal 2 but not signal 1 - also not acitvated but nothing would happen. only signal 1 leaads to inactivation and prevents autoimmunity

co-stimulator signal alone -> APC - costimulator, CD4 and T cell receptor -> co stimulator attaches to T cell -> no effect on T cell

Specific signal alone -> Tissue cell - MHC2 attaches to Tcell-> inactivates T cell (anergy)

how could Tcells be deactivated = same cell is recognized by a pathogen ->reason for autoimmune response

danger signal leads to activation - how induced - PRRs! enitial encounter

adaptive immunity only possible with innate immunity

Nonbacterial protein AG -> unstimulated macrophages dont deliver s costimulatory signal to T cells recognizing nonbacterial AG -> anergic T cell

Bacteria -> bacteria stimulate macrophages to deliver a co-stimulatory signal to Tcell recognizing bacteria AG -> proliferation and differentiation of T cell specific for bacterial protein

Bacti + nonbacti protein -> bacteria stimulate macrophages to deliver a co-stimulatory signal to T cells recognizing nonbacterial AG -> proliferation and differentiation of T cell specific for nonbacti protein => Autoimmune/autoreactive Tcell activated

stimulation of naive t cell / Recognition -> Proliferating T cell/ proliferation/Differentiation -> Active effector T cells kill virus-infected cells / Effector function

how would a AG presenting cell would recogize a T cell? -> lot of viruses doesnt be present in cytosol, bc not present in AG presenting cell

DC express high levels of B7 and can activate naive CD8 T cell -> Activated CD8 Tcell makes IL-2, driving the own proliferation and differentiation => strong stimulus => direct CD8+ T cell activation

APC stimulates effector CD4 T cell, which in turn activates the APC -> Activated APC ecpresses CD40 and 4-IBBL, which costimulates naive DC8 Tcell => weak stimulus => CD4+ t cells necessary fot the activation of CD8+ T cells

uptake of extracellular AGs ( by phagocytosis) and presentation on MHC-1 molecules => activation of CD8+ T cells by “cross-presented” AGs -> contradiction

mainly DCs are able to cross-present AGs!

The only fate to present MHC1 peptides is death. for naive Tcells-> doesnt apply to a amission naive T cell -> co pathways death, CD4 others.

not all AG presenting cells can be infected by a virus

virus infected cell -AG capture/ infected cells and viral AGs picked up by host APCs -> Cross-presentation -> T cell response

solution: describes a leekiness between both pathways

in absence of CD8-> CTL recognizes and binds virus infected cell -> CTL program target for death, inducing DNA fragmentation -> CTL migrates to new target -> Target cell dies by apoptosis

perforin - make holes in the membran e

granuoles

immulogical synapse -> highly specific. only virus infected cells are killed!!

same mechanism of the NKcells

Immunisuppressive drugs: e.g. cyclosporin: binds to and inhibits calcineurin and thereby the translocation of NFAT to the nucleus -> organ transplants, auto immune diseases.

why does the drug work specific on NFAT? -> is specific as possible but does also express all T-cell/Bcells

immune specific, but not disease specific

AP-1, MAP-Kinase, NFKB -> also in other sytems. NFAT-only in lymphnotes -> calcineucin activates phosphatase -> specific Neuclear factor of activated T cells - immunecell specific

IL2 gene - activated by joined reaction of transcription factors

cyclosporin inhibits calcineucin

autokrin - self acting, cell produces IL-2, consumes it

parakrin - induced by a cell and acts on the neighboring cell

endokrin - hormones which are released on the whole body

resting T cells express only a moderate-affinity IL-2 receptor (IL-2Rß and y chains only; also lower treshold now) -> activated T cells express a high-affinity IL-2 receptor (IL-2Ra, ß and y chains) and secrete IL-2 -> binding of IL-2 to its receptor signals to T cell to enter the cell cycle -> IL-2 induce t-cell proliferation

naive CD4 T cell (uncommitted) -> proliferation T cell ->immature effector T cell (TH0)

1. TH1 cell - activates macrophages

1. TH2 cell - activates B cells to make neutralizing AB; has various effects on macrophages

virus infected cell - always dead

CD4 - macropage interaction (TH1) or AB producing cell (TH2)

CD8 - perforin and Granzymes are the ones released

CD4 - TH1 - activate macrophages - IFNy

TH2 - activate Bcell - IL4; IL-5 eosinophil; IL-10; TGF -> downregulation TH2 response; IL6 - innate but promotes AB production

Th0

TH1. TH2

INF-y. IL4

TNF-a. IL5

TNF-ß. (IL6)

IL10

TGF-ß

IL-2 - Tcell prolifration

IFNY- macrophage activation; (induction of MHCII expression); inhibition of TH2 cells; Activation of CD8+ T cells - e.g. viral infection

TH1 inflammatory —-IFN-y production—> macrophage—positive feedback—> activated macrophages/killing of intracellular bacti —-IL2 production—-> inflammatory TH1 cell.

IL-4 -> b cell activation and proliferation class swithc to IgE; Induction of MHC-2 expression; macrophage inhibition

IL-5 -> Eosinophil activation; Class switch to IgA

IL-6 -> B cell activation; release of acute phase proteins

IL-10 -> macrophage inhibition, inhibtion of TH1 cells

TGF-ß -> macrophage inhibiton

IL-10 & TGF-ß => modulate

TH2-> class switch: IgM/igM -> B cell -> IgE

TH2 -> stimulation -> eosinophil

TH2 -> stimulation -> mast cell

allergy development & immunity against parasites

how is it insured that just the target cell dies? -> close contact = only the granulos are released.

collision and nonspec. adhesion-> specific recognition redistributes cytoskeleton and cytoplasmic components of T cell -> release of granules at site of cell contact -> contact area

Recognition phase: clonal selection; differentitaion to effector cells; clonal expansion

activation phase : clonal expansion

effector phase: TH & CTL; Plasma cells (Produce AB); Cellular and humoral immune response; elimination ot pathogen starts

Homeostasis: T and B cell apoptosis; elimination of pathogens starts to flats

Memory: matrue B and T cells there