NK cells play important roles in both innate and adaptive immunity. As part of the innate immune system, NK cells help control viral infections through cytotoxic killing of infected cells and by secreting cytokines like IFNγ and TNFα that activate macrophages. NK cells express activating and inhibitory receptors that allow them to distinguish healthy "self" cells from infected or abnormal cells. The balance of signals through these receptors determines whether an NK cell mounts an immune response. NK cells also contribute to adaptive immunity by developing a form of immunological memory, responding more rapidly upon secondary exposure to pathogens.
4. OVERVIEW OF NK CELL
NATURAL KILLER CELL
If there is no MHC-1 on intestinal
Cells, what will happen to then ?
ACTIVATION - IL-12, IFN-ᵞ
MATURATION - DNN THYMUS,
INTRACELLULAR PATHOGEN
MATURE IN BONE MARROW
ANTIGEN - DO NOT NEED
EXPOSURE TO ANTIGEN
SP. ANTIBODY - NO MEMORY
ABILITY
MARKERS- NO CD4, CD8, CD3
YES- CD16,56
Intracellular Extracellular
Pathogen Pathogen
TH0
IL-12 IL-4
IFN-ᵞ
×
TH1 TH2
×
IL-2 IL-4,5,6,10,13
IFN-ᵞ TNF TGF-ß
IL-12 ,IFN- ᵞ
8. INTRODUCTION
• NK cells (group Innate lymphoid cells) – large(15µm), granular, bone
marrow-derived lymphocytes that display cytotoxic activity against a wide
range of tumor cells in the absence of any previous immunization with the
tumor.
• Named “NK cells” - initial notion - do not require activation to kill cells that
are missing “self” markers of MHC class 1
• NK cells donot express TCR or B cell surface immunoglobulins.
NK cell
9. NK CELL CD SURFACE MARKERS AND FUNCTIONS
CD NUMBER FUNCTION
CD2 ADHESION MOLECULE & BINDS CD58
ACTIVATES NK CELLS
CD11b PHAGOCYTOSIS OF iC3b COATED PARTICLES
CD11c SIMIAR FUNCTION TO CD11b
CD16 IMMUNE COMPLEX INDUCED CELLULAR
ACTIVATION, ADCC
CD56 HOMOTYPIC ADHESION
10. • NK cells - 5%–10% of total lymphocytes in human Peripheral
Blood
• NK cells differ from NK1-T phenotypically, by origin and by
respective effector functions
• Sometimes NK1-T cell activity promotes NK cell activity by
secreting IFNγ
11. NK1-TCELL
CHARACTERISTIC
OF BOTH NK & T
CELL
LIKE TCELLS THEY HAVE
TCR INTERACT WITH MHC
LIKE MOLECULE CD1
RATHER THAN MHC 1 OR 2
LIKE NK THEY HAVE
CD16 (VARIABLE LEVEL)
& OTHER RECEPTORS &
THEY KILL INFECTED
CELLS
A popln
of NK1-T cells - rapidly
secrete large amounts - cytokines -
support antibody prodn
by B cells,
inflammation and the development
and expansion of CTLs.
TLR signaling- result in
the recruitment and
activation of macrophages,
NK cells, and dendritic
cells, key agents in the
presentation of antigen to
T cells
12. Role of NK cell in Innate & Adaptive
immunity
• Nk cells - effectors of innate immunity
• NK cell - role in adaptive immune response
• The ability for NK cells in both the innate and adaptive immune
response - important in research utilizing NK cell activity and
potential cancer therapies
13. ROLE IN INNATE IMMUNITY
• NK cell–dendritic cell crosstalk
-NK cells can kill iDCs, NK cells and DCs reciprocally activate
one another during an immune response
14.
15. NK cell function in adaptive response
Ability to generate memory cells following a primary infection
Consequent rapid immune activation
Response to succeeding infections by the same antigen
(Fundamental to the role T and B cells play in the adaptive immune
response)
Despite prior belief - NK cells play no role in the adaptive immune
responses, been found to undergo expansion, contraction, memory
maintenance and recall
16. NK cell receptors
• NK cell receptors - differentiated based on function.
• 2 different categories of receptors
TWO RECEPTOR MODEL
Inhibitory receptors –
delivers inhibition signals to
NK cells
Activation receptors-
delivers activation
signals
17. ACTIVATION
RECEPTORS
Ig SF
CD16 (FcγRIII),
CD28,
KIR2S, KIR3S,
NCR (NKp30, 44, 46),
ILT-1 (Ig-like
transcript 1)
Cyto R
CD25 (IL-2Rα)
CD122 (IL-2Rβ)
IFN-α/βR
TNFRSF
CD27
C-lectin
CD69
CD94/NKG2C, E
CD161
NKG2D
Ly49D, H, P
CD16
SPECIES- H, M
MOTIF/ADAPTOR-
ITAM/FcᵞR
LIGAND- IMMUNE
COMLEX-ADCC
CD28-
SPECIES- H,M
MOTIF/ADAPTOR-
YXXM/P13K
LIGAND- CD 80,86
CD226
SPECIES- H
LIGAND-
CD112,CD155
KIR2S/KIR3S
SPECIES- H
MOTIF/ADAPTOR-
ITAM/DAP12
LIGAND – HLA 1
CD25(IL-2Rß)-
H
LIGAND- IL-2
CD122(IL-
2Rß)
H,M
JAK-STAT
IL-2,15
IFN-αßr
H,M
JAK –STAT
LIGAND-
TYPE1 IFN
CD27
H,M
TRAF
CD70
CD69
H,M
CD94/NK
G2C-
H,M
ITAM/DA
P12
HLA,E
LY49
M
ITAM/DA
P12
H-2
NCR(NKP30,44,4
6)
H,M(NKp46)
ITAM/DAP12
VIRAL
HAEMAGGLUT
ININS
-
20. • Opposing-signals model - balance betn
activating signals and
inhibitory signals - enable NK cells to distinguish healthy cells
from infected or cancerous ones.
IRs- in cytoplasmic domain structural
motif ITIMs
As IR bind MHC-1 ITIMs phosphorylated
on tyrosine residues – phosphorylated
ITIMs bind and promote the action of
cytoplasmic protein tyrosine phosphatases.
These phosphatases remove the phosphate
group of from tyrosine residues of various
signaling molecules thus block the
activation of NK Cells Through Activation
Receptors
26. Function
CYTOTOXIC MECHANISMS (THE ‘WEAPONS’)
• NK cells are cytotoxic
small granules in their cytoplasm contain proteins - Perforin and proteases
known as Granzymes
Upon release - close proximity to a cell , perforin forms pores in the cell
membrane - target cell - an aqueous channel through which the granzymes ,
associated molecules enter - inducing either apoptosis or osmotic cell lysis
Lysing a virus-infected cell- potentially only release the virions,
whereas
Apoptosis leads to destruction of the virus inside.
α-defensins, an antimicrobial is also secreted by NK cells, directly kills
bacteria by disrupting their cell walls analogous to neutrophils
27. PERFORIN
PORE FORMING
PROTEIN
ENCODED BY
PRF1 GENE
CYTOLYTIC
PROTEIN FOUND IN
GRANULES CTLs &
NK CELLS
UPON DEGRANULATION
INSERTS ITSELF INTO
TARGET CELL PLASMA
MEMBRANE, FORMS PORE
OR ENDOSOME
ALLOWINGRANZYMES TO
ENTER TARGET CELL
CYTOPLASM
THE LYTIC MEMBRANE-
INSERTING PART OF
PERFORIN IS MACPF
DOMAIN
Granulysin
- (humans)
function
similarly to
perforin
29. GRANZYME
B
Protease located in
cytoplasmic granules
of killer cells
Cleaves after
aspartate residues
that have the
sequence: Ile/Val-
Gly/Met/Glu-X-Asp-
X-Gly
Caspase 3 and 8 are
direct substrates for
granzyme B
Caspases are
cysteine proteinases
involved in
apoptosis
Other granzymes in
granules
(granzyme A, K, M)
33. Cytokine-induced NK and CTL
activation
• Cytokines play a crucial role in NK cell activation
• Cytokines- stress molecules released by cells upon viral infection,
they serve to signal to the NK cell the presence of viral pathogens.
• Cytokines involved in NK activation include IL-12, IL-15, IL-18,
IL-2, and CCL5.
• NK cells - activated in response to interferons or macrophage-
derived cytokines.
34. Nk cells respond to IL-12 produced by macrophages & secrete
IFN- γ, which activates the macrophages to kill phagocytosed
microbes
35. NK CELL CYTOKINES
Interferon gamma (IFN-γ):
- activation, growth and differentiation of T, B, NK cells and macrophages
-promotes Th1 differentiation
-enhances MHC expression on APC
-some direct anti-viral activity
Tumour necrosis factor alpha (TNF-α):
-paracrine and endocrine mediator of inflammation
-regulates growth and differentation of a wide variety of cells
-selectively cytotoxic for many transformed cells
36. Granulocyte/macrophage colony stimulating factor
(GM-CSF):
-survival and growth factor of HSCs
-differentiation and activating factor for granulocytic and
monocytic cells
-growth factor for endothelial cells, erythroid cells,
megakaryocytes and T cells
37. • They serve to contain viral infections while the adaptive immune
response is generating antigen-specific cytotoxic T cells that can
clear the infection.
• NK cells work to control viral infections by secreting IFN γ and
TNF α.
• IFN γ activates macrophages for phagocytosis and lysis, and TNFα
acts to promote direct NK tumor cell killing.
• Patients deficient in NK cells prove to be highly susceptible to early
phases of herpes virus infection.