Chapter 9- Adaptive immune response BOOK

Naive T cells

Have not yet encountered a specific antigen

Effector T cells

Some effector T cells are directed to the sites of pathogen entry while others are directed to interact with B cells to produce antibodies

Primary immune response vs secondary

primary: initial antigenic response=primary

Subsequent reencounter with the same pathogen in a secondary immune response

CD4 T cells

Naive Cd4 t cells can differentiate into different types of efefctor T cells such as T helper 1 and 2, 17, FH and reg

TFH

T Follicular helper

Activate MHC class II bearing target cells, such as macrophages, mucosal epthelial cells and B cells

Treg

Regulatory T cells

Inhibit initiation and extent of immune activation

Memory T cells

Can retain effector functions and persist for months to years at substantially higher numbers than their naive clonal precursors

Where are the adaptive immune responses initiated?

Secondary lymphoid organs- lymph nodes, spleen, mucosa associated lymphoid tissue MALT- ex Payers Patches

Consists of different parts where B and T cells are concentrated

Contain macrophages, dendritic cells, stromal cells

Marginal zone B cells

Do not recirculate

a region located at the interface between the red and white pulp. They serve as a first line of defense against blood-borne pathogens, particularly encapsulated bacteria.

Germinal center

B cells are proliferating and undergoing somatic hypermutation

Follicular dendritic cells

Not from bone marrow

Specialized stromal cells that are limited to B cell zones

Produce chemokine CXCL13 which acts on the receptor CXCR5 on B cells to attract the to follicles

HEV

High enothelial venules

Found in T cell zones→ thick endothelial cell lining → specialized for the recruitment of lymphocytes into lymph nodes

Peyers patches

Lymph node like structures interspersed at intervals beneath gut epithelium of the small intestine

Sample antigens from intestinal lumen→ provides sites for B cells to synthesize IgA

How do B and T cells enter sec lymphoid organs?

Enter via blood→ directed via chemokines to B and T cells (secreted by stromal cells)

Enter via HEV→ cell cell interaction→ NOT antigen specific but governed by cell adhesion molecules

(Except the spleen→ enter via marginal sinus)

HEV interaction: Selectin interaction → activation of integrins by chemokines

Selectins

Important for guiding lymphocytes to particular tissues → called homing

Naive T cells→ mediated by L-selectin → marker for these cells in T cell zones

Cell surface molecules→ bind carbohydrates on endothelial cells

CCR7

Chemokine receptor expressed by naive T cells, regulatory T cells

CCR7 + chemokines→ activates LFA-1→ increasing affinity to ICAM→ higher avidity→ arrestthe T cell on the surface→ enables crossing of HEV and enter lymphoid tissue

FRCs

Fibroblast reticular cells

Creates a 3D network → fascilitates interactions of naive T and dendritic cells

T cell in lymph node

1. T cells enter lymph node cortex from blood via HEV

2. T cells not activated leave via cortical sinuses

3. T cells activated by APC dendritic cells → cant leave T cell zone→ proliferation

4. Differentiation to effector cells→ T cells exit via cortical sinsues

Dendritic cells

Central players between innate and adaptive immunity

They sense pathogens- innateimmunity

They activate naive T cell responses→ adaptive immunity

Antigen presenting cells

All express MHC class 2 + present peptides

Dendritic cells→ activates naive T cells for diff

Macrophages→ to receive help from effector and memory T cells like cytokines or surface molecules→ to kill microbe

B cells→ present to T FH cells to GC responses

Dendritic cells

Express 2 main co stimulatory molecules glycoprotreins B7.1 and B7.2 (CD80/CD86)

They deliver signals to naive T cells expressed CD28

Can also present self peptides

Very important with co stimulatory activity→ if no→ no immune response→ use adjuvants (with ex bacteria)

3 kinds of signals involved in activation of naive T cells by APCs

1. MHC+ antigen peptide recognized by TCR and CD4

2. C28 on T cell bind B7 molecules on APC→ proliferation+survival

3. Cytokines activate cytokine R→ differentiation

ALL 3 signals are NEEDED for expansion + differentiation of naive T cell→ effector cell

Activation of T cells to effector cells

Leads to the expression of alfa chain of IL-2R/CD25

Production and response of IL-2 is important whenT cells become activated

Gamma and beta chains are already expressed

T Reg cells already express IL-2Ralfa→ can outcompete naive T cells→ act as a sink for IL-2 by limiting its availability to other cells→ when T cells have IL2Ralfa→ competition

CTLA-4

B7 can bind → Inhibits and dampen of immune response→ no T cell activation or clonal expansion

CTLA-4 inhibits activation by outcompeteting CD28 → higher affinity

Are expressed AFTER activation of T cells

CD40L

TNF family

Expressed on the surface of T cell after initial activation

Signals via CD40 on APCs to upregulate B7→ clonal expansion

CD4 and CD8 cells can be activated BY SAME APC

Lead to licensing

CD4 cell bind to same cell bound to CD8→ further activation of the APC=licensing

CD4 cell produce CD40L which induced the APC to produce B7 + CD70→ which bind CD8 cell→ AMPLIFYING CD8 response

Also produces IL-2→ enhance memory

CD4 t cells can differentiate into

Several distinct subsets

Helper or regulatory cells

TH1,Th2,Th17, T follicular helper, regulatory cells

TH 1,2, 17 are defined by the combinations of cytokines they produce

TH1

Produce IFN gamma

Intracellular microbes→ mostly mycobacteria

Th1 recognize microbial antigen on macrophage→ activation of macrophage further by IFN-gamma

TFH develop in concert with TH1→ promote B cell class switching that favors opsonizing IgG antibodies

TH2

Produce IL4,5 and 13

Control infections by parasites, helminths→ promoting eosinophils, basophils and mast cells

TFH develping in concert promotes class switching of B cells to produce Ig E.

TH17

Produce Il-17A and IL-17F, IL-22

Extracellular bacteria and fungi and amplify neutrophilic and monocytic responses

Cytokines activate barrier epithelial cells→ producing antimicrobial peptides

TFH developing in concert promote class switching to opsonizing IgG2 and IgG3

TFH

Develop in concert with TH1 and TH2 or TH17

Produce some cytokines the same as above

Influences the class switching of B cells to generate immunoglobulin isotypes

Also produce Il-21→ B cell maturation and support of germinal center response

Helps to produce high affinity anitibodies

T Reg

Promote tolerance to antigens→ produce TGF-beta + IL-10

TFH + T reg development favor production of IgA

Prevents T cell mediated immune response

2 ways of development:

• During positive selections Treg is developed, in thymus→ natural T reg

• Naive CD4 T cells develop into T reg, in secondary lymphoid organs→ called induced T reg

STAT

Family of Transcription factors

Cytokines direct the development of effector cells by activating different member of the STAT family

T reg cells

pTreg vs tTreg cells

PTreg→ in secondary, express FoxP3, need RA for development

tTreg→ develop upon antigen recognition in thymus, express Fox P3

Cytokines suppression

The subsets of CD4 cells can produce cytokines that can negatively regulate the development of effector activity of other subsets

T reg function

Preventing autoreactive immune responses

tTreg→ develop during + selection in thymus→ constitutive expression of IL-2Ralfa. L selectin, CRR7 and CTLA-4

pTreg→ arise in periphery from CD4 cells, express SAME as tTreg

FoxP3→ important transcription factor prevents production of IL-2, cannot produce it themself→ need other cells to do it

CTLA-4 remove B7 on APC cells

Effector T reg

eTreg

Produce IL-10→ inhibits expression of MHC molecules and co-stimulatory molecules

Also inhibits cytokine production of APC

Effector molecules of T cells

1. Cytotoxin→ stored in granules in cytotoxic cells, need regulation due to not specific→ trigger apoptosis in any cell

2. Cytokines or membrane associated proteins→ synthesized by all effector T cells, ex CD4 cells→ restriced to MHC bearing cells class 2. Auto or paracrine or long distance

Polarization

Immunological synapse ensures polarized release of cytokines so that they are concentrated at the site of contact with the target cell

What cell surface molecules do most effector T cells express?

Members of the TNF family

Ex: TnF-alfa, lymphotoxins (LTs), Fas ligand (CD178), CD40 ligand

Fas

Contains a death domain

FasL+ Fas (CD95)→ induces death by apoptosis of Fas bearing cell

Cytotoxic T cells

Kills target through apoptosis induced by extracellular signals or by the lack of signals for survival

2 pathways for apoptosis: Activation of proteases

-extrinsic pathway→ death receptors→ death inducing signaling complex (DISC)

-intrinsic pathway→ induced through noxious stimuli or lack of growth factors

Proteases involved in apoptosis

Specialized→ called caspases

Synthesized as pro-caspases→ catalytic domain is inhibited→ activated by other caspases→ cleavage

2 types: initiator caspases cleaves other

Effector caspases initiates cellularchangesassociated with apoptosis

Intrinsic pathway

Triggered by the release of cytochrome c from mitochondira→ triggers the activation of caspases→ forms a apoptosome

Cytotoxic effector cells

Calcium dependent release of cytotoxic granules upon recognition of antigen on the surface if target cell

Granules= modified lysosomes containing 3 classes of cytotoxic effector proteins: perforin, granzymes, granulysin

These proteins are stored in cytotoxic granules in a active form→ but no actions in granules.

Perforin

Forms pores which both causes direct damage and forms a conduit → contents of granules can be released here to the target cell

Granzymes

Activate apoptosis once delivered to target cell cytosol via pores formed by perforin

Granulysin

ANtimicrobial activity, at high C is able to induce apoptosis

Serglycin

Cytotoxic granules also contain serglycin

Proteoglycan which acts as a scaffold, forms a complex with perforin and granzymes

Cytotoxic T cells are…

Serial killers

Kill one cell at a time

Reorient their golgi + microtubule organization center to focus secretion to one point of contact with target cell