benita nkt cells
DESCRIPTION
immunologyTRANSCRIPT
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n tur l killer
t cells
M. Benita Nancy Reni, 1.7.14
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NK T cell
NKT cells represent a distinct lineage of T cells that express an invariant T
Cell Receptor (TCR) and share a number of cell surface markers in common
with NK cells.
NKT cells are non-polymorphic CD1molecule-restricted T cells and are
activated by glycolipid antigens presented by CD1d.
They constitute only approximately 0.1% of all peripheral blood T cells.
The ability of these cells to produce Th1 and Th2-related cytokines has
implicated them in several fields, including transplantation, tumors,
autoimmunity, and allergy.
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can promote cell-mediated immunity to tumors and infectious organisms,
including bacteria and viruses, yet paradoxically they can also suppress the cell-
mediated immunity associated with autoimmune disease and allograft rejection.
Furthermore, in some diseases, such as atherosclerosis and allergy, NKT cell
activity can be deleterious to the host. Although the precise means by which these
cells carry out such contrasting functions is unclear,
NK T cell
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Classification
Type I cells(Classical NKTs)
invariant NKT (iNKT)
Type II cells
(Non-classical NKTs) NKT-like cells
CD1d dependent Yes Yes No
-GalCer reactive Yes No No
TCR chainV14-J18 (mice); V24-
J18(humans)
Diverse, but some V3.2-J
9, V8 (mice)Diverse
TCR chainV2, V7, and V8.2(mice);
V11 (humans)
Diverse, but
some V8.2(mice)Diverse
NK1.1 (CD161)
Positive (resting mature);
negative/low (immature or
post-activation)
Positive and negative Positive
Subsets CD4+, DN(mice); CD4+, CD8+, DN
(humans)
CD4+ and DN (mice) CD4+, CD8+, and DN
IL-4 production Yes Yes No
IFN-production Yes Yes Yes
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NK markers
NK1.1 (CD161) marker of activation (can also be expressed on activated
Tcon)
CD56 (NCAM)
neural cell adhesion molecule: important for cell adhesion
Expression of CD161 and V24J18 TCR can be used to identify
mouse and human NKT cells, respectively.
Expression of transcriptional repressor, Promyelocytic Leukemia
Zinc Finger (PLZF), in immune cells differs between mice and
humans.
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NK markers
In mice, PLZF is highly expressed in immature CD1d-resrictedinvariant NKT cells and a subset of gamma delta
(Vg1.1+Vd6.3+) T cells.
In humans, PLZF is expressed in NK cells, gamma delta T cells,
as well as CD4+ and CD8+ T cells. PLZF exists as a homodimer or in complex with PLZP, known to
be involved in the development of NKT cells, NK cell function,
cellular quiescence and growth suppression.
PLZP has also been shown to inhibit gene expression inducedby retinoic acid receptor.
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Development
NKT cells arise in the thymus from a common precursor pool of CD4+CD8+double-positive thymocytes that have undergone random TCR gene rearrangement and expression.Expression of a TCR that binds with appropriate avidity to MHC class II or I (MHCII or MHCI; plus self-peptide) on thymic epithelial cells leads to the positive selection ofconventional CD4+T cells (green) or CD8+T cells (blue), respectively. Thymocytes that express a TCR that binds to CD1d plus self-lipid or glycolipid antigen, expressed by otherdouble-positive thymocytes, enter the NKT cell lineage (red). Once selected, NKT cell precursors undergo a series of differentiation steps that ultimately results in the NKT cellpool. At least four distinct NKT cell development stages have been defined through differences in expression of CD24, CD44 and NK1.1; these are controlled by a series oftranscription factors (blue). NKT cells that emigrate from the thymus mostly do so at stage 2 and progress to stage 3 in the periphery. Some mature thymic NKT cells also migrateto the periphery but many remain as long-term thymus-resident cells. CD4NKT cells seem to branch from CD4+NKT cells at approximately stage 1 of development, althoughthey possibly do so earlier (dashed arrow). A separate pathway of NKT cell development gives rise to an IL-17-producing subset (NKT-17; orange) that seems to be regulated by
the transcription factor ROR-t. Much less is known about the developmental sequence of these cells (dashed arrow and question mark).
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Intracellular signalling pathways that regulate
NKT-cell development.
Natural killer T (NKT)-cell selection and maturation requires a range of signalling events that are not essential for conventional T-cell development, in addition to factors thatare common to both T-cell and NKT-cell development. The unique signalling requirements of NKT cells are not fully understood, but the three main intrinsic pathways thatlink most of the known mutants that affect NKT-cell development are depicted. These include the SLAM SAPFYN pathway, the T-cell receptor (TCR)-signalling cascade(particularly the classical nuclear factor- B(NF- B) pathway) and the interleukin-15 (IL-15) pathway. AP1, activating protein 1; c, common cytokine-receptor -chain; DOK,docking protein; I B ,inhibitor of NF- B ;IKK2, I Bkinase 2; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; PKC ,protein kinase C ;RASGAP, RAS GTPase-
activating protein; SAP, SLAM-associated protein; SHIP, SRC-homology-2-domain-containing inositol-5-phosphatase; SLAM, signalling lymphocytic activation molecule;STAT, signal transducer and activator of transcription; ZAP70, -chain associated protein kinase of 70kDa.
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NK T cell; a jack of all trades
While NK T cells primary function is cytotoxicity (trait of NK and CTL lineages) they also have
helper characteristics as the secretion of IFN- or IL-4 induces T helper cells to differentiate intoeither TH1 or TH2 cells.
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iNKT
Unique subpopulation of T lymphocytes
true T cells: CD3 and TCR
semii invariant TCR diversity
also express some NK markers: CD161, CD56 Dependant for CD1d for antigen presentation.
Potential for both effector and regulatory functions -double-edged sword of the immune system
Very rare in the peripheral blood Implicated in autoimmunity, tumour immunity/control,
GvHD
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CD1d molecules
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Antigen Lipid antigens: lipids, glycolipids, lipopeptides
Bacterial: sphingomonas pg
Mycoplasma (TB & leprosy)
Isoglobotrihexosylceramide (iGb3):
> a glycolipid in the thymus that if present will
select for iNKT cells (iGb3 deficient mice aredeficient in iNKT)
Gal-Cer
galactsyleramide synthetic glycolipid derived from
a a marine sponge > strongest known agonist for iNKT
Glycolipid from tumour cell membranes
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Antigenic recognition by iNKT
iNKT cells recognise lipid antigens via non classicalCD1d molecules
CD1: related to MHC I but structural differences
Group I: CD1a, CD1b, Cd1c
Group II: CD1dGroup II: CD1d
> the lipid interacts with the antigen binding groove
of CD1a
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iNKT cells functions
Potential for both effector and regulatory
functions
double-edged sword of the immune system
form a bridge between innate and adaptive
immunity
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Effector function: cytotoxicity
Direct:
antigenic stimulation of iNKT cells leads to perforin,
FasL and TRAIL dependant direct cytotoxicity by the
iNKT cellsthemselves.
Indirect:
iNKT cells produce INF which stimulates cytotoxicCD8 and NK cells.
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Regulatory function
Produce large amounts of regulatory cytokines: IL4 Th2 response (humoral immunity)
IFN-, and TNF Th1 (cell mediated immunity)
Can skew towards Th1 or Th2 or both!!!!
Regulate the function of DC, macrophages, B cells, T
cells, NK cells
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NKT and autoimmunity
Scleroderma:
restricted TCR diversity with absence of TCR V 24
SLE:
skewing towards IL4 secreting cells with reduction in NKT
numbers and production of B cells that produceantiDSDNA
Type I diabetes:
NOD (non obese diabetic) mice are deficient in NKT
onset of diabetes can be prevented by adoptive transfer of
thymic iNKT cells
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NKT and cancer
Tumour cell clearance and prevent metastasis
increased NK cell cytotoxicity (IFN- mediated) - mousemodels of colon adenocarcinoma melanoma lung carcinoma
Tumour surveillance NKT deficient mice (lack CD1d or TCRJ 18) exposed to
carcinogens developed tumours faster than immunocompetentmice
NKT cells contribute to tumor immuno-surveillance viaendogenous IL-12 pathway, early IFN
NKT cells promote effective responses in anti-tumor
vaccinesystems. CD1d down-regulated on tumor cells from human
patients
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Activation by -GalCer leads to potent tumor
rejection, (pulsed DCs even better)
Tumor rejection due to administration of exogenous
IL-12 is CD1d dependent
NKT cells contribute to tumor immuno-surveillance
via endogenous IL-12 pathway, early IFN
NKT cells promote effective responses in anti-tumor
vaccine systems
CD1d down-regulated on tumor cells from human
patients
NKT and cancer
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iNKT and GvHD
Mouse models: that low iNKT associated with
GvHD
Adoptive transfer can abrogate GvHD
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Thank you..