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
3) TC cell dissociation
4) Target cell obliteration (destruction)
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
3) TC cell dissociation
4) Target cell obliteration (destruction)
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).
3) TC cell dissociation
4) Target cell obliteration (destruction)
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