Immunology final

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MAT.126 5.5

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Ch1DefiningDifferentiatedInstruction

da Lisa Batkiewicz

Innate immunity

da Buchro Duera-oh

Need CD28 to produce Jun...Jun and Fos together form AP-1

proliferation, differentiation of T cell --> effector T cell

*****If it was CD8, it would be the same thing. End would be cyto T lymphocyte. binds all same structures but MCH class I and CD8

T cell entering lymph node--> effector T cell

Circulating T cell enters high endothelial venue in lymph node

binding of L-selectin to GlyCAM-1 and CD34 allows rolling interaction

LFA-1 activated by cytokines bound to extracellular matrix

LFA-1 bind tightly to ICAM-1

diapedesis: lymphocyte leaves blood and enters lymph node and goes to T cell region where Das are

from T cell region, 2 possible directions

Binding: T cell Receptor+ CD3+ CD4+ CD28 (co receptor binds to C7)

CD3, CD4, CD28 binding MHC molecule + peptide

SMAC T cell synapse

signals produced by CD4 to activate Lck

once interaction occurs, Lck is a kinase

LCK interacts with Zap70

phosphorylation of tyrosines CD3 group

NFAT

DAG

RAS

MAPK pathway

FOS

PCK-OMEGA

NFkB

No binding of TCR to MHC class II + peptide

has receptor for S-1-P moves to efferent lymphatic vessel

goes to next lymph node ends up in duct and blood stream where it can go to 2ndary lymphoid tissue

Activation B/T cells in one mucosal tissue committed to defending all musosal tissues

Naïve b and t cells enter blood-naïve lymphocytes enter 2ndary tissues peyers patch and mesenteric lymphnodes release CCL21 and CCL19→bind chemokind CCr7(naïve b and t cell) →endothelial venules→2ndary lymphoid tissues

•Effector cells (active B/T cells) →recirculate from lymph nodes (PP) → alpha4:beta7 expressing B and T cells (big part to take it to mucosa) →attach MADCAM1 on endothelial tissues in blood stream near mucosa→CCR9 follows CCL25→attachment to mucosal epithelium

FC receptors

FcalphaRI

monomeric IgA

FcgammaRIIB

inhibiting

B1: mast cells, B cells MO, neuts, eosinophils

FcgammaRIIA

activating-->phagocytosis

FcgammaRIII

ADCC only used on NK cells, why? Why not CD8? NK cells part of innate/nonspecific. T cells have TCR and because of all different proliferation and differentiation they go through, they have highly specific TCR. NK cells use Fc receptors and get specificity through antibodies. CD8 T cells use TCR to find cells vs. NK cells nonspecific and just have Fc receptor which binds to constant region of antibody and variable region decides where to attack

NK cells, ADCC (antibody dependent cell mediated, cytotoxicity…using antibodies to help use cells to kill other cells), IgG1 or G3

FcgammaRII

3 have lower affinities for IgG than FcGammaR1

• FcgammaR1

IgG Monocytes, MO, DC During inflammation, also neutrophils and eosinophils IgG3→IgG1→IgG4 Main purpose is to help phagocytosis Antibody mediated opsonization

Naïve B cells→ travel to lymph node→Find TFH cell also specific for pathogen→BINDING HAPPENS BETWEEN MHC/TCR, B7/CD28, MHC/CD4) cognate pair B + T cells (medullary cords) → proliferate→ moves from medullary cords to B cell region→ TFH and B cell disconnect→ Centroblasts (isotype switching, somatic hypermutation, Ig poor on surface→ proliferate→ centrocytes→ competing for AG sites on FDCs (to increase infinity for antigen) Leave the germinal center to find TFH again with all the receptors again mhc and tcr→cognate pair again→ cytokine signals to either go to memory cells (IL-4), plasma cells (IL-10) or back to centroblasts.

Primary Response B cell

Cognate pair or conjugate pair (B-T cell margin to medullary cords)

B-cell and TFH cell

MHC class II and antigen peptide

TCR complex

CD40L gets expressed on TFH and CD40L goes to CD40 on B cell

LFA-1 and ICAM synapse

TFH cytokines and cytokine receptors on B cells

Proliferation and differentiation of B cells then to either plasma, memory cells or migrate to 2ndary follicle in B cell zone

Migrate to 2ndary follicle

proliferation of B cells

centroblasts rapidly divide

centroblasts-->centrocytes in light zone along with FDC

these 2 interact due to AG on extension of FDC and BCR...affinity maturation occurring

competition between centrocytes to bind to antigen on FDCs...ones able to bind have highest affinity

BCR bind to antigen?

internalizes receptor mediated endocytosis

processing and presentation of MHC class II

move to T cell area, interacts with TFH cells (same as above with CD40 etc.)

can also bind to self antigen

energy and possible apoptosis

B7-CD28 monovalent binding of BCR

signals for survival for 1. return to GC 2. plasma cell using IL-10 to alumina propria, medulla cords or bone marrow 3. IL-4 to memory cell

Apoptosis

somatic hypermutation and isotope switching (AID) associated with dark zone of germinal center

Plasma cells: IL59, IL-6 come from TFH BLIMP-1-bell to stay in lymph node or bone marrow to plasma

T lymphocyte development

derive from Bm and must undergo gene rearrangement to produce antigen receptors

T cells go to thymus from BM before rearrange t-cell receptor genes

gene rearrangment: one alphabet and one lambda:gamma receptor

Driven by Notch1

induces protease to cleave intracellular domain/release from plasma membrane. translocated to nucleus and turn on expression of genes for T cell development by removing repressive transcription factors

IL-7 receptor

double negative thymocyte (no CD4 OR CD8)

Notch1 rearrangement

rearrange Beta, gamma, delta

pre-T cell receptor (forms complex with CD3)

CD3 sends signals for proliferation (RAG 1 AND 2)

alpha chain rearrangement (gamma, delta)

Alpha:beta TCR--> MHC and self peptides

more alpha rearrangement if possible free Vs and Js still availalbe

back to MHC and self peptides

strong binding/moderate binding (best)

dendritic cells expressing AIRE (which turns on tissue specific genes) and macrophages

test for tissue specific self-peptides

cell dies

first allele, then second...still not productive then no further rearrangements

B lymphocyte development

in bone marrow, stroll cells interact with very early B cells (homatopoietic stem cells that turn into B or T lymphocytes)

Early pro-B then D-->J rearrangement due to Pax5...heavy chain always rearrange first

TDT expressed.

After D-->J then V-->DJ

large pre-B cell stage

lambda5 PreV

Mu combining with surrogate light chain and IgBeta/IgAlpha

signal sent that results in positive selection...survival

Rag1 and Rag2 stop being produced

proliferation/cell division

pre B cell stage and get light chain rearrangement starting...RAG1 and 2 expressed

production of IgM to surface by Igalpha and beta

sends signal to survive and RAG 1 and 2 not expressed

immature B lymphocyte

apoptosis

Naive Immature B cell

bloodstream

lymph nodes HEV L selection (b-cell)

primary follicle of B cell region (FDC)

secrete CXCL13 (B cells move to FDCs)

FDC b-cell interaction

FDCs bind to LT produced by B cells to produce B-Aff

maturation and survival B cells (IgM/IgD)

encounters Ag on FDC

start of process B cell activation

BCR multiple receptor complex Igalpha and Igbeta and tryp

SYK binds adjacent IgB

LFA-1 on TFA bind ICAM-1 on B cell

synapse forms conjugate pair

END

antigen activated B cell

Move to B-T cell margin due to production of CCL219 by TFH bind CCR7

B cell internalize Ag through RME process and present peptide on MHC class II

Activated TFH

TFH more CD40 binds to CD40 on B cell

coreceptor Cd8+, CD19, CR2

CR2 binds iC3b

CD19 activated

CD19 phosphorylated by SYK

signal

encounters Ag away from FDC then Ag has C36 on surface

Heavy chain/light chain rearragnemtn

Heavy chain rearranges first

not always productive

• Reading frame is not always correct • Unproductive rearrangement (wrong) • Productive rearrangement (right)→H chain protein

productive

There is always a leader and a transcription start site

One of the J’s rearranges to one of the Ds anything between that DNA rearrangement gets lost.

Vh, Vh, Vh, Vh, Dh, Dh, Dh, Dh, Jh, Jh,

One the Ds can bind to the Vh variable too but everything between gets cut out

Generation of junctional diversity during gene rearrangement: 1. Generation of junctional diversity 2. RAG complex cleaves the heptamer RSS from D and J segments to yield DNA hairpins 3. RAG complex opens hairpins by nicking one strand of DNA, generating palindromic P-nucleotides 4. N-nucleotide additions by TdT 5. Pairing of strands 6. Unpaired nucleotides are removed by exonuclease 7. Gaps are filled by DNA synthesis and ligation to form coding joint

RLR/interferon pathway

recognition of viral nucleic acid by RIG-1-like receptors (RLR) initiate inflammatory response

viral replication in cytoplasm produces uncapped RNA with a 5' triphosphate

RLR binding to viral RNA induces association with MAVs and dimerization

FADD/TRADD activate NFkappaB

NFkappa B causes synthesis and secretion of inflammatory cytokines

One site on MAVs engages TRAF6 which leads to activation of IRF3 and secretion of type 1 interferon.

Type 1 interferons (INFalpha and INFbeta) cause interferon response

3 major functions. 1. induce resistance to viral replication in all cells 2. increase expression of ligands for receptors on NK cells 3. Activate NK cells to kill virus-infected cells

complement pathway

C5 activation by C5 convertase

C3b2Bb on pathogen surface, C5 binds to C3b component and is cleaved into C5a and C5b fragments.

C5b initiates the assembly of terminal complement to form membrane-attack complex

C5b, C6, C7 bind to pathogen surface. C8 and C7 undergo conformational change to expose hydrophobic sites...insert into membrane

induces polymerization of C9 to generate transmembrane channel

DAF and MAP distrust C3 convertase C3bBb on human cell surface. causes C3b to dissociate and leads to inactivation

recruitment of inflammatory cells

C3 is hydrolyzed which activates C3 and binds factor B. Cleavage of B by serine protease factor D produces a soluble C3 convertase called IC3Bb

iC3Bb activates C3 molecules by cleavage into C3b and C3a. C3b can become attached to microbial surface

Factor H binds to C3b and changes conformation to cleavage by factor I

iC3b fragment of C3 remains attached to the pathogen surface but cannot form a c3 convertase

Properdin (factor P) binds to C3bB to extend its lifetime on microbial surface

fixation of complement

C3 cleaved to produce a large C3b and small C3a fragments

C3b is reactive and becomes attached to pathogen surface (thioester bond), marking the pathogen as dangerous

C3a recruits phagocytic cells to site of infection

Naive T cell---> CD8 T cell killing virally infected cells

Naive T cell interacts with DC presenting its specific antigen

plc-gamma cleaves PIP2 to DAG and IP3

IP3

ip3 increases Ca2+-->activates calcineurin

NFAT activated

DAG:

activates RasGRP, activates MAP kinase cascade

RAS-induced kinase induces and activates Fos

activated protein kinase C

activates NFkappaB

changes pattern of gene expression

CELL DIVISION, PROLIF., DIFFERENTIATION TO EFFECTOR T CELLS

Immune responses

Adaptive

selection process

any cell in bone marrow

immature B cell

if responds to self cells: either apoptosis or receptor editing

Positive selection

no receptor editing

immature to mature B cell

FDCs

postitive life signal; otherwise die in 3 days

2ndary lymphoid organ

B cell follice

negative selection

MHC present self antigen

lives

thymus, DC, Macrophages

receptor editing

Positive selection occurs in thymus

Recognize self MHC

dies

Lives

Generation of diversity

T cell development

Beta chain

alpha chain

rearrange many times

DN4--> DP

2 on each chromosome

thymus

DN2

pTalpha

B cell development

heavy chain

light chain

Immature B: do heavy/light chain produce functional binding site?

many rearrangements

small pre-b cell stage

Large preB--is chain functional?

early pre B to large pre B cell

Lambda5, VproB

2 (4 if counting DJ and VD seperate)

Lymphocytes

bone marrow

antibodies

T lymphocytes (activate B cells)

ACTIVATION of T cell

Process MHC class II

CD40L:CD40

IL-2 binds to IL-2R

Proliferation

2ndary lymphoid tissue

CD4 T cells

activate Macrophage and dendritic cells

need inflammatory response

Lymphoid tissues

T cell trafficking (4 steps)

diapedesis

chemokines

CCL21 & CXCL12

chemokine

CCL21

adhesion

integrins

LFA-1

Rolling

selection

L selection

APC

Clonal expansion

differentiation

cytokines

TYPES of what cell can turn into

TH1 activate macrophages help B cells produce Ab

CD8 cyto t cells kill infected cells

ways to activate CD8 cytotoxic T cells

Dendritic Cell

B7--> activate CD8

ADC

B7 & IL-2

CD4 T cell

IL-2

CD8 proliferation

TH2 parasitic/allergies help B cells produce Ab

TH17 enhance neutrophil response

TFH aid in isotype switching of B cells

TReg inhibits immature DCs

survival

CD28:B7

activation

MHC:TCR

present antigen

dendritic cell, macrophage

Thymus

Helper cells

cytotoxic T cells

Memory cells

B lymphocytes

Bone marrow

Activation Of B-cell

cross-link antigen

CR2

MHC class II

MHC class I

alpha 1 and 2

more than 10 AA

beta 1

CD40

alpha 1

CD3 on antigen

B cell

affinity maturation

Positively selected B cell

affinity for antigen

T cell help

B cell cross linking

plasma cells or memory cells

negatively selected B cell

APOPTOSIS

centroblasts

isotype switching

T cell

somatic hypermutation

point mutation

FDC's --> better selection

Centrocytes

germinal center

Memory B cell

Plasma cell

Innate

compliment cacase (3 pathways)

Classical pathway

Alternative pathway

C3bBb

C3bBb3b

C3b from other pathways

Lectin Pathway

C4b2a3b

Mannose binding lectin

C4b2a

The interaction between B cells and T follicular helper (TFH) cells is crucial for the immune response, particularly within lymph nodes. TFH cells express CD40L, which binds to CD40 on B cells, signaling them to proliferate and differentiate into plasma or memory cells.