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Unconventional (T)-lymphocytes
Arpad Lanyi, LSB 2.201
[email protected]
Main Characteristics of innate lymphocytes
Subsets:
• γδT-cells
• iNKT cells
• MAIT (mucosa associated invariant Tcells)
Main characteristics:
• Very rapid response to pathogens or to
tissue dysregulation
• No MHC-restriction
• Non-reactive to peptide-MHC complexes
• Antigen presentation by MHC-like proteins
• May especially be important early in life,
when the adaptove system is not fully
functional
Innate lymphocytes:
γδT cells
B-cells, αβ T-cells and γδ T-cells are remarkably
similar by appearance
αβ T-cell
γδ T-cell
B-cell
Innate Immune cells in the murine skin
Langerhans cells (Langerin)
γδ T-cell receptor
Dendritic Epidermal
T-cells (DETC)
merge
Human Intraepithelial lymphocytes have a very limited
receptor repertoire
Intraepithelial lymphocytes
TCR γ1δ1
Immunol rev 2007
γδ T Cells and the Lymphoid StressSurveillance Response
Adrian C. Hayday
http://dx.doi.org/10.1016/j.immuni.2009.08.006
A distinct population of T-cells expresses a second class of TCR
with γδT cell receptors
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The two types of receptors are similar,
Similar gene rearrangement process
Small to medium diversity
CD8-/CD4- (double negative)
None-peptide small molecules, stress
proteins, presentation by class I like
molecules
• Abundant in tissues
• Maintenance of homeostasis, tissue
repair
γδ T-cells
•MHC-independent, CD1c and CD1d dependent.
•Double megative.
•Comprise about 1-5% of the T-cells found in the circulation, but can
be the dominant (20 to 50%) T-cell population in epithelial tissue
(intestine and dermis).
•A population that is expanded in intra- (Mycobacterium tuberculosis
and Listeria monocytogenes) and extracellular infections (Borrelia
burgdorferi) and certain disease states such as celiac disease.
•Many of the receptors are shared with NK cells
Development of unconventional T cells in the thymus
γδ T-cells, NKT-cells
Subsets of γδT-cells: Vγ9:Vδ2 receptors of
blood γ:δ T cells recognize phosphoantigens.
• γγδTcells in various tissues express different γ:δ TCR.
• Killing and cytokine production (IFNg for example)
IPP, made by
the host cells
• γ:δ T cells recognize phosphoantigens
HMBPP,
Produced by Bacteria
Drug approved for the treatment of
osteoporosis patients
Butyrophilin 3A1 on tissue cells binds phosphoantigens and
presents them to γ:δ T cells.
Butyrophilin 3A1
The endothelial protein C receptor (EPCR) is a ligand for Vγ4:Vδ5 T cells.
• Recognition of virus-infected cells (e.g. CMV)
• In response to CMV infection the Vγ4:Vδ5
population is expanded.
• Also respond to tumor cells mainly in the early
phase of tumor development.
VγVδ1 T-cell receptors recognize lipid antigens
presented by CD1d
Sulfatide is a glycolipid made by human cells and is
abundant in the intestinal epithelium. The upper panel
shows sulfatide being bound by CD1d in the endoplasmic
reticulum and then transported to the cell surface. There
the sulfatide is recognized by the antigen receptor of a
Vγ:Vδ T cell.
the chemical structure of sulfatide.
• IFN gamma (CD27+)
• IL17 (CD27-)
The role of γδ Tcells in tumor development
• Both pro- and anti-tumor effects possible
• Anti-tumor effect was usually dependent on
stress-induced sugnals
• Antitumor effect: mediated via IFNγ, TNF, Th1 and
CTL
• Pro-tumor effect: IL17, recruitment of Tregs,
MDSC and mactophages which produce IL1β,
IL23…. Induction of more IL17…..
Receptor–ligand interactions mediating tumour cell
recognition by human γδ T cells.
Innate lymphocytes with αβ TCR
iNKT cells
Activation of NKT cells requires two signals, one
from the T-cell receptor and the other from a
cytokine receptor.
• αβTCR, but with very limites specificity and
usage of TCR gene segments (Vα24-Jα18:
Vβ11 ). Glycolipid, phospholipid recognition (αgalactosyl ceramide, α-Gal-Cer)
• Develop in the thymus
• Master regulator transcription factor is (PLZF)
promyeloytic leukemia zincfinger protein
• Selected on double-positive cells in the thymus
• Lipid antigens are presened by CD1d
• CD1d is constrantly recycling between the
membrane and the endosomal vesicles
• Saponins allow removal of self-lypids and
loading of foreign lipids
• NK-cell activation requires at least two signals.
In responding to changes in self and microbial lipid antigens, NKT cells orchestrate an
immune response through interactions with several different types of cells of innate and
adaptive immunity.
The NKT cell can have conjugate interactions
withvarious cell types.
• NK cells,
• Dendritic cells,
• Macrophages, and neutrophils of innate immunity
and also the B cells of adaptive immunity.
• Cytokine secretion, NKT cells can also influence the T
cells of adaptive immunity (may produce IFNγ or IL4
among others.).
NKT cell immunoregulatory axis.
• Anti-tumor effect
• NKT-deficient mice exhibited significantly
increased susceptibility to ethylcholanthrene(MCA-) induced sarcomas and B16F10
melanoma tumors
• effect reversed by the administration of liverderived iNKT cells during the early stages of
tumor growth
• iNKT, IFNγ and CD8-dependent process.
• May indirectly have anti-tumor effect by
killing tumor—associated macrophages
(TAMs)
• Solid tumors do not express CD1d
• Selective
R H Wiltrout
Immunotherapy (2011) 3(10), 1167–1184
Manipulating iNKT Cells for Cancer
Treatment
Mucosa-associated invariant T (MAIT)
• MAIT cells αβ comprose 1-10% of T-cells in blood, and 2040% in the liver.
• MAIT cells recognize by-products of riboflavine synthesis
called pterins (humans aquire it from diet of microbiota.
• αβTCR, but with very limites specificity and VαJα usage
(Vα7.2Jα33).Lipid presentation via MR1, an
unconventional MHC class I molecules.
• Highly conserved receptor and lipid presentation suggwst
coevolution of the receptor and the pathogen.
MAIT cells recognize by-products of the synthesis of riboflavin called pterins.
Other MHC class Ib proteins encoded outside the MHC region
MR1 – molecules are expressed on various cell types
(MHC Related-1)
They have polar antigen binding site
They present microbial riboflavin (vitamin B2)
metabolic products and byproducts to mucosa
associated invariant T cells (MAIT)
Corbet AJ et al.: Nature, 2014 vol509, 361-
Many vitamin biosynthetic pathways are unique to bacteria and yeast.
Mammals can only acquire riboflavin, so MAIT cells use these metabolites to
detect microbial infection.
MAIT cell numbers and maturation are
dependent on the microbiota.
1-10% of T-cells in the blood
20-40% in liver
Thank you