Adaptive immunity

2. 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)
An adaptive immune response might provide lifelong protective
immunity to a given pathogen.
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
Antigen-specific responses are mediated by lymphocytes

3. Lymphocytes
B Cells
Plasma Cells
T Cells
Helper T Cells
Killer T Cells
Antibody production
Signaling
molecules
Cytotoxic
molecules

4. Lymphocyte Specificity
Lymphocyte
Lymphocyte antigen receptor
(100 million different types
per person)
Foreign cell

5. Bone marrow
for B cells
Clonal
Selection
The somatic
evolution of
B and T cells
populations
Thymus for T
cells
XX
XX
Antigen binding in the
bone marrow leads to B
cell deletion (death). Strong
antigen binding in the
thymus leads to T cell
deletion
periphery
clonal expansion
Antigen binding in the
periphery can lead to
activation (other signals
are required, too)

6. 1*
3
4
2
The self/nonself discrimination (or tolerance) is “learned” in the soma
*Numbers represent the 4 panels in the previous slide

7. TCR complex
TCR
-8 transmembrane protein
-V,D,J segment are highly polymorphic.
-TCR responsible for Ag recognition
-CD3 responsible for signal transduction
through ITAMs
ITAMs
ITAMs

8. Similarity between TCR
and Ig
Bind antigen
Have variable region
Constant region
Each binding site is a
heterodimer (composed of 2
different chains)
TCRs act only as receptors
Igs act as receptors and
effector molecules (soluble
antigen-binding molecules)

10. TCR
•
•
αβ
95% of T lymph
Ɣδ
5% ot peripheral T and NK
Phenotype:DP or SP
Site:thymus,LN,spleen
Ag :processed and presented
by MHCI or MHC II
DN or CD8
Epidermis,epith of tounge,intestine
Effector function;
Th,Tcyt
Can recognize unprocessed Ag
without MHC presentation
Protect the integrity of wound
healing
Cytolytic effect
Produce Ɣ interferon

11. TCR Gene Rearrangements
TCR gene rearrangment

12. TCR Gene Rearrangements

13. TCR Genes and Proteins

14. Alternative D region usage

15. heptamer
J
Spacers and nonamers not shown
D
D
heptamer
J
CDR3

16. TCR Diversity

17. 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.

18. MHC restriction
T cell system is heavily biased towards
recognizing peptides bound to selfMHC 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.

19. One specificity per T cell (one antigen and one restriction specificity combination ).
For example, let’s look at MHC class I restricted T cells
Class I
β 2 microglobulin is
not encoded in
MHC
MHCa (HLAa)
Ba Ca
Aa
6 possible restriction specificities per individual
Anti-X restricted to Ba
Bb Cb
Ab
MHCb (HLAb)
Anti-X restricted to Bb
Anti-X restricted to Ca
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.
Anti-X restricted to Cb
Anti-X restricted to Aa
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
Anti-X restricted to Ab
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).
The more common HLA nomenclature is B*0702 Cw*0203
A*0209

20. 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.

21. T-cell ontogeny
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)

22. Positive selection for self MHC restriction
Negative selection are anti-self MHC restriction

23. Thymic selection of T cells
cortico-medullary
junction
cortex
subcapsular
region
medulla
tingible body
macrophage
interdigitating
cell
thymocyte
thymic epithelial cell
macrophage
blast cell
POSITIVE SELECTION
Interaction with MHC
class I or MHC class II
on cortical epithelium
cortex
medulla
NEGATIVE SELECTION
Interaction with MHC class I or
MHC class II + self peptide
(dendritic cells, macrophages)

24. MHC restriction
T cell system is heavily biased towards
recognizing peptides bound to selfMHC 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.

25. 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

26. Avidity hypothesis
Not differential signaling
No positive
selection
Positive
selection
No negative
selection
nothing here so this
cannot be correct
No positive
selection
Negative
selection
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 selfpeptides 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.

27. T cells bind to the combination of foreign peptide* and MHC.
T cells cannot bind foreign peptide alone nor MHC alone.
T cell
T cell
T cell
peptide
TCR
MHC
TCR
binding?
Yes
No
No
*derived from foreign
protein by antigenprocessing

28. 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.

29. How do T cells
recognize antigens?

30. Nominal antigens & superantigens
Nominal antigens
Superantigens
Require processing to peptides
Not processed
TcRα and β chains are involved
in recognition
Only TcR β chain involved
in recognition
<1 in 105 T cells recognise
each peptide
2-20% of T cells recognise
each superantigen
Recognition restricted by an
MHC class I or II molecule
Presented by almost any
MHC class II molecule
Almost all proteins can be
nominal antigens
Very few antigens are
superantigens
Suggests a strikingly different mechanism
of antigen presentation & recognition.

31. Superantigens
T cell
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
Vβ
Vα TcR from
MHC A
haplotype
Class II from
MHC A to Z
haplotypes
APC

32. A big picture:
How do T cells
recognize antigens?
MHC molecule
TCR

33. Tcell activation
(3 signals)

34. Signal 1 : TCR recognises MHC/antigen complex
(TCR complex contains CD3, CD45 etc…)
T cell activation
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-Receptors
RESULT
New gene transcription (IL-2, IL-2r….)
Proliferation & expansion of the specific clone

35. Signal 1 :TCR recognises MHC/antigen complex+coreceptors

36. T cell Activation by an Activated
APC
IL-1
IL-6
IL-12
CD28
“Signal 3”
B7
CD4 ++
CD4
T cell
T cell
LPS
T Cell
Receptor
“Signal 2”
TLR4
“Signal 1”
Peptide
MHC II
Antigen Presenting Cell (APC )

37. T cell Activation by an Activated APC
IL-1
IL-6
IL-12
IL-12 Receptor
CD28
“Signal 3”
B7
CD4 ++
CD4
T cell
T cell
LPS
T Cell
Receptor
“Signal 2”
TLR4
“Signal 1”
Peptide
MHC II
Signal 1: Specificity
Signal 2: Activation
Signal 3: Differentiation
Antigen Presenting Cell (APC)

38. The 2-Signal Model of Lymphocyte
Activation
CTLA-4
B7 (CD80/86)
B7 (CD80/86)
APC
CD28
TCR
MHC
↓Activation
↑Activation
Recognition
II
CD2
CD58 (LFA3)
↑Activation
CD40
Adhesion
CD40L
CD4 +
T CELL
T
Cell

39. The Immunological
Synapse: Co-Receptors
For T cells: co-receptors bind to MHC of MHCAg 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 tail
B cell co-receptor: CD19, CD21, CD81
complex
CD21 recognizes activated complement
 CD19 constitutively associated


40. T Cell Recognition

41. Molecular Interactions of Helper T Cells and APC
CD4+ T Cell
CTLA-4
CD28
p56 lck
CD3
CD40L
Cα C
β
V
α
CD2
ζ ζη η
γδ ε
TCR
Vβ
CD45
LFA-1
VLA-1
peptide
B7
B7
CD80/CD86
CD4
CD40
MHC II
APC/ B cell
LFA-3
ICAM-1

42. Antigen presentation - T cells are co-stimulated
Signal 1 antigen & antigen
receptor
Th
APC
ACTIVATION
Signal 2
B7 family members (CD80 & CD86)
CD28
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.

43. T helper cells costimulate B cells
Two - signal models of activation
Signal 1 antigen & antigen
receptor
B
Y
YY
CD40
MHC class II
and peptide
ACTIVATION
Th
Signal 2 - T cell help
T cell antigen receptor
Co-receptor (CD4)
CD40 Ligand (CD154)

44. Mechanism of co-stimulation in T cells
Low affinity IL-2
receptor
IL-2
Antigen
1
IL-2
IL-2Rα
IL-2Rα
Resting T cells
Express IL-2 receptorβ and γ chains but no
α chain or IL-2
Signal 1
NFAT binds to the promoter of of the
α chain gene of the IL-2 receptor.
The α chain converts the IL-2R
to a high affinity form

45. Arming of effector T cells
Clonal selection and differentiation
APC
T
IL-2
Effector
T cell
Activation of NAÏVE T cells by signal 1
and 2 is not sufficient to trigger
effector function, but…..
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
How can this cell give help
to, or kill cells, that express
low levels of B7 family
costimulators?

46. Effector function or Anergy?
Clonally selected,
proliferating and
differentiated
T cell i.e. ARMED sees
antigen on
a B7 -ve epithelial cell
IL-2
The effector programme
of the T cell is activated
without costimulation
Armed
Effector
T cell
Armed
Effector
T cell
This contrasts the
situation with naïve T
cells, which are
anergised without
costimulation
Naïve
T cell
CD28
TcR
Co-receptor
Kill
Epithelial
cell
Epithelial
cell
Epithelial
cell

47. Anergy
Antigen
Naïve
T cell
1
Signal 1
only
IL-2
IL-2Rα
Epithelial
cell
Self peptide epitopes presented
by a non-classical APC e.g. an
epithelial cell
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.

48. Antigen
TCR
TH2 activation,
for example
Plasma cell
The two signal model for lymphocyte activation
(antigen alone is insufficient)
Here, signal 2 is TCRmediated, antigen specific
recognition; not shown.
(see similar slide later)
(Mature dendritic cell)
(Mature naive T cell)
Proliferation and differentiation of
the T cell to effector function
(Armed effector T cell)
Proliferation and differentiation of
the B cell to effector function
Memory B cell
B cell
activation,
for example
Signal 1 comes from recognition of antigen
Signal 2 comes from another (activated) cells

49. TCR signaling

50. TCR complex
TCR
-8 transmembrane protein
-V,D,J segment are highly polymorphic.
-TCR responsible for Ag recognition
-CD3 responsible for signal transduction
through ITAMs
ITAMs
ITAMs

51. T Cell Activation: Early Steps
Prior to cell-cell
contact,
dephosphorylation
predominates:
ITAMs
unphosphorylated
CD45 phosphatase
complexes with CD4
Maintains activationcompetent stateremoval of Cterminal of Lck
From Nel, J. Allerby, Clin Immunol, 2002

53. B
Menu
F

54. TCR Signaling: CD4
enhancement, Lck
activation and
recruitment and
activation of Zap-70.

55. TCR signaling
PLCγ1
CD4
CD28
Zap70 Lck
Fyn
Tec
(PMA)
IP3 + DAG
Ca++
Lck
Shc
Grb2
PIP2
(ION)
CD45
SOS
Ras
PKC
MAPK
calcineurin
NFκB
NFAT activation
Lymphokines gene expression
PTK

56. Figure 6-16

57. T cell differentiation

58. Effector T Cells
Composed of three kinds of cells:
CD8+ TC cells
cells
CD8
TH 1 & TH 2 cells
 T H1 & T H2 cells

Characterized by:
Less Stringent activation requirements CD28B7 interaction NOT necessary for activation
 Increased expression of cell-adhesion
molecules



increased expression of CD2 & integrin LFA1
Production of effector molecules:

60. T Helper

61. 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?

62. T helper Cell Differentiation
• Type 1 response
Th1
IFNγ
TNF-b
IL 2
• immunity to mycobacteria
• inflammation
• rheumatoid arthritis, diabetes
Th0
Th2
IL4
IL13
IL10
• Type 2 response
• IgE antibody responses
• Immunity to some parasites
• allergic diseases

63. γ IFN,TNF
IL2
+
+
IL2
+
TH1
IL12/IL6
+
APC
pathogen
local
microenvironment
CD40
TH0
B7
TH1
IFN γ
-
-
IL4
IL2 +
TH2
+
IL10
TH2
IL4/IL10
-
+
IL4

65. B
Menu
F

67. Cytotoxic T

68. Focus: Cytotoxic T cells
Cytotoxic T
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

69. Generation of Effector Cytotoxic T cells
Cytotoxic T
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 T cell precursors (CTL-P’s) need IL-2 produced
C
from TH1 cells for proliferation


Memory TC cell precursors may produce enough IL-2
to self-proliferation

70. Cytotoxic T cell activation

71. Figure 14-2

72. Cytotoxic cell’s Granule
Cytotoxic T attach steps Mediated Homicide
1) Conjugate formation
2) Membrane attack
3) TC cell dissociation
4) Target cell obliteration (destruction)

73. Figure 14-6

74. Cytotoxic T cell 1-Granules Mediated pathway.
2- Fas-FasL pathway.
Cytotoxic T cell’s Granule Mediated Homicide
1-Granules Mediated pathway
1) Conjugate formation
Recognition: TCR-Ag-MHC I interaction
 Embrace: LFA-1 receptor (T cell) binds to ICAM’s
C
on target cell membrane

2) Membrane attack
3) TC cell dissociation
4) Target cell obliteration (destruction)

75. 1) Conjugate formation
2)Cytotoxic Tattack Granule Mediated Homicide
Membrane cell’s

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)

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

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

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

79. Figure 14-11: Caspase Cascade

80. 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

81. 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

82. Cell Organization of C-MER
Cytotoxic cells
Cells with direct cytotoxic activity:

Antigen specific


+
CD8+ Cytotoxic T cells (TC C cells or CTL’s)
Cytotoxic T cells (T cells or CTL’s)
Nonspecific
Natural Killer Cells (NK cells)
Natural Killer Cells (NK cells)
 Macrophages

Cells that mediate the delayed-type
hypersensitivity reactions (DTHR):

CD4+ TH cells
TH1 cells
TH1 cells
T 2 cells
 T H2 cells
H


83. Tof T-cell Effector Molecules
cell functions
Functions
Mediate target-cell destruction by TC cells:



Fas ligand (membrane-bound)
perforins (soluble)
granzimes (soluble)
TC cell
Promote macrophage activity:



TNF-β (soluble & membrane-bound)
INF-γ (soluble)
GM-CSF (soluble)
T H1
TH2
Play role in B-cell activation by TH2 cells:


CD40 (membrane bound)
IL-4, IL-5, IL-6 (soluble)

84. 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.

85. 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

86. The Control of Activated CD4+ T Cells by Regulatory T cells
NKT cells/
CD4+CD25+ cells
CD4+CD25- cells
Apoptosis
peptide/APC
(- )
TH1 CD4+ cells
IL-12/
IFN-γ
(- )
IL-10
(- )
IL-4
Resting CD4 T cells
IFN-γ
Activated CD4 T cells
(- )
TH2 CD4+ cells
Regulatory immunity
CD4/CD8 interactions
CD8 or CD4
suppressor
effector
CD8 or CD4 suppressor
precursor
L. Chess 2002

87. Regulatory T cell
Suppressor Cell
Natural Treg
Regulatory cells
RegulatoryTT Cell
Subsets
Murine Markers
CD8+
CD4+, CD25+
CTLA-4+,
GITR+, Foxp3+
(intracellular)
Adaptive Treg
CD4+, CD25 -,
Foxp3Tr1
CD4+, CD45Rb lo
Th3
CD4+, CD45Rb lo
Invariant NKT cell Invariant TCRα
(Vα14-Jα281),
CD4+, CD8-,
NK1.1+
Proposed Mechanisms of Inhibition
Recogn ition of Qa-1:peptide on activated CD4+ T
cells → induction of cytotoxicity
Cell-contact dependen t but not antigen-specific;
Ligation of B7 on effector cells; IL-2
sequestration; CTLA-4 interaction with IDO →
tolerogenic DCs; IL-10 & TGF-beta production
Cell-contact dependen t but not antigen-specific
inhibition
Cell-contact independen t; IL-10 & IL-4 secretion
Cell-contact independen t; TGF-beta secretion
CD1d:glycolipid complex recogn ition; IL-10
secretion

88. Natural Killer (NK) Cells
Functions
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:

INFγ:
 Affects phagocytic and microbial activities of macrophages
 Influences T 1 cells vs T 2 cells commitment of development
H
H
3-First line of defense in viral infections

Number of NK cells peaks ~3 days after infection

89. Comparison between NK and T Cells
Similarities


Common early progenitor (Lymphoid progenitor)
Express some common membrane markers:



CD2
75 kDa β 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

90. 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

91. Natural Killer (NK) Cells
Express inhibition and activation receptors on cells surface

Many inhibition and many activation receptors create an opposingsignal 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-α, 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

92. 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!!!

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

94. What is NKT Cells?
Immunology Today November 2000 Vol21 No.11 573

95. Characteristics
 Express
both T cell receptors and NK1.1
receptors — hence its name.
 Respond
to glycolipid antigens presented by
CD1d
 CD1
restricted rather than MHC restricted
 CD4+
or Double negative, in mice
 Secrete
large amounts of either IFN-γ, IL-4,
TNF
 Lack
immunological memory

96. 1.Control of infection
Current Biology Vol 15 No 11,2005

97. 2.Bridging innate and
acquired immunity
VOLUME 4 NUMBER 12 DECEMBER 2003 NATURE IMMUNOLOGY

98. Models of Memory
Lymphocyte Development
Ag +
Co-stimulation
Effector Cell
CLASSIC THEORY
Activated cell in Environment X
Ag
Naïve cell
Activated cell in Environment Y
Memory Cell
Ag
Effector Cell
Precursor
KLINMAN LINEAGE HYPOTHESIS
Effector Cell
Ag
Ag
Memory Cell
Precursor
Memory Cell
Effector Cell

99. Ag +
Costimulation
Ag
Apoptotic Death
95 to 99%
1 to 5%
Naïve Cell
Activated cell
Effector Cell
LINEAR DIFFERENTIATION MODEL
Ag +
Costimulation
Memory Cell
Activated cell
Activated/Effector Cell
Ag
Effector Cell
Ag
Naïve Cell
Memory Cell
Memory Cell
Memory Cell
DIMINISHING POTENTIAL MODEL