Adaptive immunity

An adaptive immune response might provide lifelong protective immunity to a given pathogen.

Adaptive Immunity:

Specific Immune Response (e.g., antibody) against a particular microorganism is an adaptive immune response. That is, it occurs during one’s lifetime as an adaptation to the presence of that particular organism. (specific means the ability to distinguish one organism from another)

Antigen-specific responses are mediated by lymphocytes

Specific immunity can be induced by a variety of substances. Things that targets of adaptive immunity are called ANTIGENS*

Things that induce an adaptive immune response are immunogens

*

Lymphocytes

B Cells T Cells

Helper T Cells Killer T CellsPlasma Cells

Antibody productionSignaling molecules

Cytotoxic molecules

Lymphocyte Specificity

Foreign cell

Lymphocyte

Lymphocyte antigen receptor

(100 million different types per person)

periphery

Clonal Clonal SelectionSelection

The somatic evolution of B and T cells populations

clonal expansionAntigen binding in the periphery can lead to activation (other signals are required, too)

Bone marrow for B cells

Thymus for T cells

Antigen binding in the bone marrow leads to B cell deletion (death). Strong antigen binding in the thymus leads to T cell deletion

X X X XX X X X

The self/nonself discrimination (or tolerance) is “learned” in the soma

1*1*

33

44

22

*Numbers represent the 4 panels in the previous slide

TCR complex

TCR-8 transmembrane protein

-V,D,J segment are highly polymorphic.

-TCR responsible for Ag recognition

-CD3 responsible for signal transductionthrough ITAMs

ITAMsITAMs

Similarity between TCR and Ig

Bind antigenHave variable regionConstant regionEach binding site is a heterodimer (composed of 2 different chains)

TCRs act only as receptorsIgs act as receptors and

effector molecules (soluble antigen-binding molecules)

TCR• α β• 95% of T lymph

Phenotype:DP or SP

Site:thymus,LN,spleen

Ag :processed and presented by MHCI or MHC II

Effector function; Th,Tcyt

Ɣδ5% ot peripheral T and NK

DN or CD8Epidermis,epith of tounge,intestine

Can recognize unprocessed Ag without MHC presentationProtect the integrity of wound healingCytolytic effectProduce Ɣ interferon

TCR Gene RearrangementsTCR Gene RearrangementsTCR gene rearrangment

TCR Gene RearrangementsTCR Gene Rearrangements

TCR Genes and ProteinsTCR Genes and Proteins

Alternative D region usageAlternative D region usage

CDR3

D

Jheptamer

D

J

heptamer

Spacers and nonamers not shown

TCR DiversityTCR Diversity

What is achieved by gene rearrangements and other mechanisms for the generation of diversity?

1. Relatively few gene segments can combine to make millions of different receptors (large repertoire) (i.e., 100s of gene segments can be assembled to make millions of variable regions for Igs and TCRs).

2. Different cells can have different antigen receptors.

3. Somatic progeny of a cell with a gene rearrangement will inherit the gene rearrangement and thus inherit the antigen recognition specificity of the parent cell.

MHC restriction

T cell system is heavily biased towards recognizing peptides bound to self-MHC that result in positive selection in the thymus that favors the survival of developing T whose TCRs have the potential to recognize peptides presented by self MHC.

One specificity per T cell (One specificity per T cell (one antigen and one restriction specificity combinationone antigen and one restriction specificity combination).).For example, let’s look at MHC class I restricted T cells

Class I

2 microglobulin is not encoded in MHC

The more common HLA nomenclature is B*0702 Cw*0203 A*0209

Anti-X restricted to Ba

Anti-X restricted to Bb

Anti-X restricted to Ca

Anti-X restricted to Cb

Anti-X restricted to Aa

Anti-X restricted to Ab

Pairs of chromosomes in each cell so each cell has two MHC loci. Within each locus are B, C and A genes encoding MHC class I proteins (polygeneic).

Because MHC is polymorphic, it is likely that the alleles for B, C and A are different.

Ba Ca Aa

Bb Cb Ab

MHCa (HLAa)

MHCb (HLAb)

X represents an antigen (e.g., a virus) however, it is not likely that all the T cells recognize the same peptide derived from X

Within an individual there will be many different T cell clones, each with one restriction specificity, responding to various peptides derived from the same antigen (or pathogen).

6 possible restriction specificities per individual

The example on the previous slide is for MHC class I. However, the principle of one restriction specificity and one antigen specificity per T cell is exactly the same for MHC class II restricted T

cells.

the antigen and the allele-specific determinants of MHC as separate entities but recognizes a new antigenic determinant formed by the combination of antigen (peptide) and MHC.

T cell development is defined by changes in

expression of three surface proteins:

TCR/CD3, CD4 and CD8

CD4-CD8- (DN)

CD4+CD8+ (DP)

CD4-CD8+ OR CD4+CD8- (SP)

T-cell ontogeny

Negative selection are anti-self MHC restriction

Positive selection for self MHC restriction

thymic epithelial cell

tingible bodymacrophage

subcapsularregion

blast cell

thymocyte

cortexcortico-medullary

junction

interdigitating cell

macrophage

medulla

POSITIVE SELECTIONInteraction with MHCclass I or MHC class IIon cortical epithelium

NEGATIVE SELECTIONInteraction with MHC class I or MHC class II + self peptide (dendritic cells, macrophages)

cortexmedulla

Thymic selection of T cells

MHC restriction

T cell system is heavily biased towards recognizing peptides bound to self-MHC that result in positive selection in the thymus that favors the survival of developing T whose TCRs have the potential to recognize peptides presented by self MHC.

Avidity: apparent affinity bet TCR and (MHC/peptide complex) which depends on

(occupancy of TCR by MHC)

High occupancy =negative selection by apoptosis

Moderate occupancy =positive selection =thymocyte growth and maturation

low occupancy =low avidity=no signal=negative selection by deletion (apoptosis)or anergy

nothing here so this cannot be correct

Avidity hypothesisNot differential signaling

Positive and negative selection can be successful if each is governed by different avidities (e.g., low avidity for positive selection; high avidity for negative selection)

Positive and negative selection occur in the presence of self-peptides but in the absence of foreign-peptides. Changing from self-peptide to foreign will change binding affinity of the TCR for MHC + peptide. Thus, a TCR with low avidity binding for self peptide + MHC will have high avidity binding for some foreign peptide + MHC.

No positive selection

No positive selection

Positive selection

No negative selection

Negative selection

T cellT cell

T cells bind to the combination of foreign peptide* and MHC.

T cells cannot bind foreign peptide alone nor MHC alone.

No No

peptide

MHC

T cell

TCR

YesTCR

binding?*derived from foreign protein by antigen-processing

In the thymus T cells undergo positive and negative selection:

Positive selection - selects T cells with T cell receptors (TCRs) that are able to interact with self MHC class I and II molecules on thymic epithelial cells

Negative selection - deletes cells that recognise self antigens expressed in conjunction with MHC class I or II molecules on thymic dendritic cells or macrophages. If the interaction is of a high affinity, the T cells will be deleted, if low affinity the T cells may escape negative selection.

How do T cells recognize antigens?

Nominal antigens & superantigens

Nominal antigens

Require processing to peptides

TcR and chains are involved in recognition

<1 in 105 T cells recognise each peptide

Recognition restricted by an MHC class I or II molecule

Almost all proteins can be nominal antigens

Superantigens

Not processed

Only TcR chain involved in recognition

2-20% of T cells recognise each superantigen

Presented by almost any MHC class II molecule

Very few antigens are superantigens

Suggests a strikingly different mechanismof antigen presentation & recognition.

Superantigens

e.g. Staphylococcal enterotoxins

Toxic shock syndrome toxin I (TSST-1)

Staphylococcal enterotoxins SEA, SEB, SEC, SED & SEE

Do not induce adaptive responses, but trigger a

massive burst of cytokines that may cause fever,

systemic toxicity & immune suppression

Severe food poisoning Toxic shock syndrome

Class II fromMHC A to Zhaplotypes

TcR fromMHC Ahaplotype

T cell

APC

V V

MHC molecule TCR

A big picture:How do T cells recognize

antigens?

Tcell activation

(3 signals)

T cell activation

Signal 1 : TCR recognises MHC/antigen complex (TCR complex contains CD3, CD45 etc…)

Signal 2 : Costimulation

1-T cell CD28 binds to B7 family (CD80, CD86),

2- CD40 and CD 40 L Signal 3 : T cell Activation by an Activated

APC(IL12,IL1,IL6)

DO NOT FORGET Co-ReceptorsRESULT

New gene transcription (IL-2, IL-2r….)

Proliferation & expansion of the specific clone

Signal 1 :TCR recognises MHC/antigen complex+coreceptors

CD4CD4++ T cellT cellCD4CD4++ T cellT cell

T Cell Receptor

Peptide

LPS

TLR4

Antigen Presenting Cell (APCAntigen Presenting Cell (APC))

MHC II

“Signal 1”

“Signal 2”

“Signal 3”

IL-1

IL-6

IL-12

CD28

B7

T cell Activation by an Activated APC

CD4CD4++ T cellT cellCD4CD4++ T cellT cell

T Cell Receptor

Peptide

LPS

TLR4

Antigen Presenting Cell (APC)Antigen Presenting Cell (APC)

MHC II

“Signal 1”

“Signal 2”

“Signal 3”

IL-1

IL-6

IL-12

CD28

B7

IL-12 Receptor

Signal 1: Specificity

Signal 2: Activation

Signal 3: Differentiation

T cell Activation by an Activated APC

The 2-Signal Model of Lymphocyte Activation

CD2

MHC

II

B7 (CD80/86)

CTLA-4

CD40L

CD28

B7 (CD80/86)

TCR

CD40

CD58 (LFA-3)

CD4CD4++ T CellT Cell

Activation

Activation

Recognition

Adhesion

Activation

APCT CELL

The Immunological Synapse: Co-Receptors

For T cells: co-receptors bind to MHC of MHC-Ag peptide complex CD4: MHC II CD8: MHC I

Co-binding of TCR and co-receptor leads to lowered threshold for activation Recruitment of Lck to TCR through association with CD4 or CD8 cytoplasmic tailB cell co-receptor: CD19, CD21, CD81 complex CD21 recognizes activated complement CD19 constitutively associated

T Cell RecognitionT Cell Recognition

V

C C

V

p56 lck

peptide

CD3CD28

CD40

LFA-3

LFA-1

ICAM-1MHC IIB7

CD40L

CD4

CD45TCR

CD2

CD4+ T Cell

APC/ B cell

Molecular Interactions of Helper T Cells and APC

B7

CTLA-4

VLA-1

CD80/CD86

Antigen presentation - T cells are co-stimulated

APC Th

Signal 1 antigen & antigenreceptor

Signal 2

B7 family members (CD80 & CD86) CD28

ACTIVATION

Costimulatory molecules are expressed by most APC including dendritic cells, monocytes, macrophages, B cells etc., but not by cells that have no

immunoregulatory functions such as muscle, nerves, hepatocytes, epithelial cells etc.

T helper cells costimulate B cellsTwo - signal models of activation

YYYB

T cell antigen receptor

Co-receptor (CD4)

CD40 Ligand (CD154)

Th

Signal 2 - T cell help

CD40

MHC class IIand peptide

Signal 1 antigen & antigenreceptor

ACTIVATION

IL-2

IL-2R

Express IL-2 receptor- and chains but no

chain or IL-2

Mechanism of co-stimulation in T cells

Signal 1

NFAT binds to the promoter of of the chain gene of the IL-2 receptor.

The chain converts the IL-2Rto a high affinity form

IL-2

IL-2R

1

Antigen

Resting T cells

Low affinity IL-2 receptor

Arming of effector T cells

APC T

Activation of NAÏVE T cells by signal 1 and 2 is not sufficient to trigger

effector function, but…..

IL-2 EffectorT cell

Clonal selection and differentiation

How can this cell give help to, or kill cells, that express

low levels of B7 family costimulators?

the T cell will be activated to proliferate and differentiate

under the control of autocrine IL-2 to an effector T cell.

These T cells are ARMED

ArmedEffectorT cell

CD28

Co-receptor

TcR

IL-2

Epithelialcell

NaïveT cell

Epithelialcell

Clonally selected,proliferating and

differentiatedT cell i.e. ARMED sees

antigen ona B7 -ve epithelial cell

Epithelialcell

ArmedEffectorT cell

Kill

The effector programmeof the T cell is activatedwithout costimulation

This contrasts the situation with naïve T

cells, which are anergised without

costimulation

Effector function or Anergy?

IL-2

IL-2R

1

Antigen

Epithelialcell

NaïveT cell

Signal 1only

Anergy

The T cell is unable to produce IL-2 and therefore is unable to proliferate or be

clonally selected.

in the absence of signal 2 causes antigen specificT cell unresponsiveness.

Self peptide epitopes presentedby a non-classical APC e.g. an

epithelial cell

Proliferation and differentiation of the T cell to effector function

(Mature naive T cell)

The two signal model for lymphocyte activation(antigen alone is insufficient)

(Mature dendritic cell)

Signal 1 comes from recognition of antigen

Signal 2 comes from another (activated) cells

Antigen TCR

TH2 activation, for example

Proliferation and differentiation of the B cell to effector function

(Armed effector T cell)

Here, signal 2 is TCR-mediated, antigen specific recognition; not shown. (see similar slide later)

B cell activation,

for example

Pla

sma

cel l

Mem

ory

B c

ell

TCR signalingTCR signaling

TCR complex

TCR-8 transmembrane protein

-V,D,J segment are highly polymorphic.

-TCR responsible for Ag recognition

-CD3 responsible for signal transductionthrough ITAMs

ITAMsITAMs

T Cell Activation: Early StepsPrior to cell-cell contact, dephosphorylation predominates: ITAMs unphosphorylatedCD45 phosphatase complexes with CD4Maintains activation- competent state-removal of C-terminal of Lck

From Nel, J. Allerby, Clin Immunol, 2002

Menu FB

TCR Signaling: CD4 enhancement, Lck activation

and recruitment and activation of Zap-70.

PIP2

IP3 + DAG

PLC1

Ca++

NFAT activation

calcineurin

CD4 CD45CD28

MAPK

Shc

Ras

SOS

Grb2

PKC

NFB

TCR signalingTCR signaling

(ION)(PMA)

PTK

Zap70 LckLck

TecFyn

Lymphokines gene expression

Figure 6-16

T cell differentiation

Effector T Cells

Composed of three kinds of cells: CD8+ TC cells

TH1 & TH2 cells

Characterized by: Less Stringent activation requirements CD28-

B7 interaction NOT necessary for activation Increased expression of cell-adhesion

molecules increased expression of CD2 & integrin LFA1

Production of effector molecules:

CD8+ TC cellsTH1 & TH2 cells

T Helper

T cell differentiation

T cells are heterogenous

Different stimulus leads to differentiation of different types of response

Th1 - very inflammatory: fight bacteria etc

Th2 - less inflammatory: fight parasites etc

Th3 - anti-inflammatory: maintain balance?

T helper Cell Differentiation

Th0

Th2

Th1

• Type 1 response

• immunity to mycobacteria

• inflammation• rheumatoid arthritis, diabetes

• Type 2 response

• IgE antibody responses

• Immunity to some parasites

• allergic diseases

IFNTNF-bIL

IL4IL13IL10

pathogenA

PC

CD40

B7

IL10

IFN IL4

IFN,TNF

IL4/IL10

TH0

TH2

TH1

-

+

-

local microenvironment

IL2+

+

+

+

-+

IL2

TH1

TH2

IL12/IL6+

IL2

IL4

Menu FB

Cytotoxic T

Focus: Cytotoxic T cells

Generated by Immune activation of TC cell precursors

Have lytic capabilities

Play critical role in recognition of altered self cells

MHC I restricted (generally) All nucleated cells in body express MHC I molecules

Cytotoxic T

Generation of Effector Cytotoxic T cells

Requires three specific signals: Signals for Activation

1-Primary antigen specific TCR(CD8+)-Ag-MHC I interaction 2-Co-stimulatory CD28-B7 interaction

(may not be necessary for Memory TC cell precursors )

Signals for Proliferation & Differentiation 3-Signal from IL-2 interaction with high-affinity IL-2 Receptor Generally TC cell precursors (CTL-P’s) need IL-2 produced

from TH1 cells for proliferation Memory TC cell precursors may produce enough IL-2

to self-proliferation

Cytotoxic T

Cytotoxic T cell activation

Figure 14-2

Cytotoxic T cell’s Granule Mediated HomicideCytotoxic T attach steps

1) Conjugate formation

2) Membrane attack

3) TC cell dissociation

4) Target cell obliteration (destruction)

Figure 14-6

1-Granules Mediated pathway 1) Conjugate formation

Recognition: TCR-Ag-MHC I interaction Embrace: LFA-1 receptor (TC cell) binds to ICAM’s

on target cell membrane

2) Membrane attack



Cytotoxic T cell’s Granule Mediated Homicide

Cytotoxic T cell 1-Granules Mediated pathway. 2- Fas-FasL pathway.

1) Conjugate formation

2) Membrane attack Cytoplasmic rearrangement

Brings Golgi and storage granules into closer proximity to target cell

Granule Secretion (exocytosis) Perforin - 65kDa monomer

Undergoes conformational change upon contact with target cell membrane which exposes amphipathic domain, enabling insertion into membrane.

Once in membrane perforins polymerize and create 5-20nm pores (w/Ca2+).

Granzyme



Cytotoxic T cell’s Granule Mediated Homicide

Figure 14-9a: Perforin pore formation in target cell membrane

Figure 14-9b: EM of perforin pores in target cell membrane

1-Granules Mediated pathway 1) Conjugate formation

2) Membrane attack Cytoplasmic rearrangement Granule Secretion (exocytosis)

Perforin - 65kDa monomer Granzyme

Binds to mannose 6-phosphate receptor and internalized into target cell. The Perforin pores allow the Granzyme to exit internalized vesicles.

Once inside cytoplasm of target cell, initiates reaction cascade culminating in activation of endonucleases which in turn digest DNA into oligomers of ~200bp (typical of apoptosis).



Cytotoxic T cell 1-Granules Mediated pathway. 2- Fas-FasL pathway.

Figure 14-11: Caspase Cascade

Cytotoxic T cell’s Fas Ligand Mediated Homicide

Fas Transmembrane protein Member of the TNF-receptor family Can deliver death signal when crosslinked with its natural

ligand Natural ligand is a TNF called Fas ligand (FasL)

2) FasL Found on the membrane of TC cells Interaction with Fas protein triggers target cell apoptosis

3) Fas-FasL interaction elucidated by experiments with perforin

Cell Death by Apoptosis

Caspase Family of cysteine proteases which cleave after Asp

residue

Normally present in cell as inactive proenzymes - “procaspases”

>12 caspases with different specificity have been identified

Cleavage of procaspase produces an active initiator caspase, which in turn cleaves other caspases.

Both Granule and Fas mediated apoptotic signaling induces the caspase cascade (Fig14-11) by activating Procaspase-8.

Results in “systematic” disassembly of the cell

Cell Organization of C-MER

Cells with direct cytotoxic activity: Antigen specific

CD8+ Cytotoxic T cells (TC cells or CTL’s)

Nonspecific Natural Killer Cells (NK cells) Macrophages

Cells that mediate the delayed-type hypersensitivity reactions (DTHR): CD4+ TH cells

TH1 cells

TH2 cells

TH1 cellsTH2 cells

CD8+ Cytotoxic T cells (TC cells or CTL’s)

Natural Killer Cells (NK cells)

Cytotoxic cells

Functions of T-cell Effector Molecules

Mediate target-cell destruction by TC cells: Fas ligand (membrane-bound) perforins (soluble) granzimes (soluble)

Promote macrophage activity: TNF- (soluble & membrane-bound) INF- (soluble) GM-CSF (soluble)

Play role in B-cell activation by TH2 cells: CD40 (membrane bound) IL-4, IL-5, IL-6 (soluble)

TH1

TH2

TC cell

T cell functions

CTL deal with antigens in the cytoplasm by killing the cells that present the antigen

TH1 deals mostly with antigen in macrophage vesicles by activating the macrophages. That is, antigens that have been phagocytized. Activated macrophages are more aggressive in killing phagocytized material and they release toxic compounds into the local environment.

TH2 deals with antigens that were bound to a B cell’s BCRs (extracellular antigens) and internalized (into vesicles). They activate B cells for antibody secretion.

For antigens to be recognized by CTLs, they must be presented in association with MHC class I.

For antigens to be recognized by TH1 or TH2, they must be presented in association with MHC class II.

Therefore, CTLs are interested in proteins synthesized inside a cell whereas TH1 and TH2 are interested in proteins that were synthesized outside of a cell but were brought into the cell in vesicles

TH1 CD4+ cells

TH2 CD4+ cells

CD8 or CD4 suppressor precursor

CD8 or CD4 suppressor effector

Activated CD4 T cells

peptide/APC

Regulatory immunityCD4/CD8 interactions

(- )

(- )

The Control of Activated CD4+ T Cells by Regulatory T cells

Apoptosis

Resting CD4 T cells

IL-12/IFN-

IL-4

NKT cells/ CD4+CD25+ cellsCD4+CD25- cells

(- )

(- )

IL-10 IFN-

L. Chess 2002

Regulatory T Cell SubsetsRegulatory T cell Murine Markers Proposed Mechanisms of InhibitionSuppressor Cell CD8+ Recognition of Qa-1:peptide on activated CD4+ T

cells induction of cytotoxicityNatural Treg CD4+, CD25+

CTLA-4+,GITR+, Foxp3+(intracellular)

Cell-contact dependen t but not antigen-specific;Ligation of B7 on effector cells; IL-2sequestration; CTLA-4 interaction with IDO tolerogenic DCs; IL-10 & TGF-beta production

Adaptive Treg CD4+, CD25 -,Foxp3-

Cell-contact dependen t but not antigen-specificinhibition

Tr1 CD4+, CD45Rb lo Cell-contact independen t; IL-10 & IL-4 secretionTh3 CD4+, CD45Rb lo Cell-contact independen t; TGF-beta secretionInvariant NKT cell Invariant TCR

(V14-J281),CD4+, CD8-,NK1.1+

CD1d:glycolipid complex recogn ition; IL-10secretion

Regulatory T cells

Natural Killer (NK) CellsFunctions

1-showed significant lysis of tumor cells.

Compose 5-10% of recirculating lymphocyte population

Involved in immune defense against virus and tumors

2-Play important role in immune regulation: Influence both adaptive and innate immunity via cytokine

production/excretion: INF:

Affects phagocytic and microbial activities of macrophages Influences TH1 cells vs TH2 cells commitment of development

3-First line of defense in viral infections Number of NK cells peaks ~3 days after infection

Comparison between NK and T Cells

Similarities Common early progenitor (Lymphoid progenitor) Express some common membrane markers:

CD2 75 kDa subunit of the IL-2 receptor *CD16 Receptor for Fc region of IgG

Differences NK cells do not develop exclusively in the thymus Do not undergo rearrangement of receptor genes

Comparison of NK and T-cell Assassination Mechanism

Similar to processes employed by CTL’s Express FasL on membrane surface Contain Granules of perforin and granzimes Target cell degradation occurs via perforins and granzymes

Different from CTL’s cytotoxicity NK always cytotoxic, do not need to be activated to produce granules Do not express Ag specific T-cell receptors or CD3 Recognition of target cells is NOT MHC restricted NK immune response generates no immunological memory

No greater immune response upon secondary infection

Natural Killer (NK) Cells

Express inhibition and activation receptors on cells surface Many inhibition and many activation receptors create an opposing-

signal model. The balance between the opposing signals is believed to enable NK to

differential between healthy and infected cells (Fig 14-14)

Additional NK activator signals can be delivered by soluble factors

TNF-, IL-12, and IL-15

NK cells may target cells that produce aberrant MHC expression Many virus-infected and tumor cells have reduced MHC expression

NK Cells Inhibitor-Receptor Superfamily

C-type-lectin-inhibitory receptor (CLIR) In humans: CD94/NKG2 - disulfide bonded heterodimer of two

glycoproteins Recognizes HLA-E on potential target cells

HLA-E serves as indicator of overall level of MHC I biosynthesis Thus CD94/NKG2 are not specific for specific HLA allele

Killer-cell-inhibitory receptors (KIR) A group of Ig-superfamily-inhibitory receptors (ISIR)

more than 50 family members have been found Specific for one or more of polymorphic HLA products

Inhibitory receptors have veto power over activation receptors Thus, cells expressing normal levels of MHC I receptors tend to

escape all forms of NK assassination. Thus cells that lack normal MHC I expression = lack of normal self

expression DIE!!!

Fig. 14-14: Opposing-signals model of cytotoxic activity

What is NKT Cells?

Immunology Today November 2000 Vol21 No.11 573

CharacteristicsExpress both T cell receptors and

NK1.1 receptors — hence its name. Respond to glycolipid antigens

presented by CD1d CD1 restricted rather than MHC

restrictedCD4+ or Double negative, in miceSecrete large amounts of either IFN-

γ, IL-4, TNF Lack immunological memory

1.Control of infection

Current Biology Vol 15 No 11,2005

2.Bridging innate and acquired immunity

VOLUME 4 NUMBER 12 DECEMBER 2003 NATURE IMMUNOLOGY

Models of MemoryModels of MemoryLymphocyte DevelopmentLymphocyte Development

Naïve cell

Ag +Co-stimulation

Activated cell in Environment X

Activated cell in Environment Y

Memory Cell

Ag

Effector Cell

Effector CellMemory CellMemory CellPrecursor

Effector CellPrecursor

Ag

AgEffector Cell

Ag

KLINMAN LINEAGE HYPOTHESIS

CLASSIC THEORY

LINEAR DIFFERENTIATION MODEL

DIMINISHING POTENTIAL MODEL

Ag +Costimulation

Naïve CellActivated cell

Ag

Effector Cell

Memory Cell

1 to 5%

Apoptotic Death95 to 99%

Ag +Costimulation

Naïve Cell

Memory Cell

Activated cell

Memory Cell

Ag

Activated/Effector Cell

Ag

Memory Cell

Effector Cell

Technology

Adaptive immunity