HLAVN MEMBRNOV FOSFOPROTEIN pp80 JE V GEMs

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http//www.img.cas.cz/mi/prednasky/bottomTre
g 2008 (Horejí, October 2008)Treg 2008
Horejsi.ppt Review Treg - Cell 2008.pdf Review
Treg - Nat. Rev. Immunol. 2008.pdf Treg subsets
- Immunity 2008.pdfTreg-Th17 Blood
2008.pdfTreg-miRNA J. Exp. Med. 2008.pdf
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DEVELOPMENT AND SELECTION OF T LYMPHOCYTES IN
THYMUS
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DENDRITIC CELLS MUST BE PRE-STIMULATED BY
DANGER SIGNALS TO ACTIVATE T LYMPHOCYTES
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BASIC REGULATORY MECHANISMTh1 x Th2
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CRUCIAL ISSUESELF-TOLERANCE
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MAJOR PROBLEM HOW TO MAINTAIN SELF-TOLERANCE
AND AVOID AUTOIMMUNITY AND OTHER
IMMUNOPATHOLOGIES?
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SIMPLE SOLUTION THOROUGH ELIMINATION OF
AUTOREACTIVE LYMPHOCYTES (NEGATIVE
SELECTION)BUT THERE ARE A LOT OF POTENTIALLY
AUTOREACTIVE T (AND B) LYMPHOCYTES IN THE
PERIPHERY!
THESE MUST BE SOMEHOW ACTIVELY
SUPPRESSED!
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HISTORICALLY1970-1985 Th (CD4), Tc (CD8),
Ts(CD8)
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Ts - A MAJOR IMMUNOLOGICAL HOT TOPIC IN
1970-1986.HUNDREDS OF PAPERS BY TOP
IMMUNOLOGISTS, BIG REVIEWS, THOUSANDS OF
CITATIONSDATA BASED MOSTLY ON GENETICS, IN VIVO
MODELS AND SEROLOGY, NOT CLONING AND RIGOROUS
BIOCHEMISTRY
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FALL AND DISCREDITATION OF TsA PAPER IN 1983
- NO I-J GENE FOUND FOLLOWING SEQUENCING OF THE
MOUSE MHC (H2) TsF COULD NEVER BE CLONED AND
RIGOROUSLY CHARACTERIZED BY MODERN
METHODSCONSENSUS MOST OF THE PREVIOUS RESULTS
WERE MISINTERPRETATIONS, ARTEFACTS, ERRORS
PRECIPITOUS DECLINE IN PUBLICATIONS ON Ts
SHAME ON Ts
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RESURRECTION (OR
REINCARNATION) AFTER 1995Sakaguchi et al, JI
19951551151Immunologic self-tolerance
maintained by activated T cells expressing IL-2
receptor a-chains (CD25).
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RECENT FLOOD OF PAPERS ON NEW SUPPRESSOR T
CELLS (CALLED MOSTLY REGULATORY T CELLS
BECAUSE OF THE Ts TABOO?)
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PROPERTIES OF THE NEW Ts Treg MINOR
FRACTION OF PERIPHERAL CD4 T CELLS (cca 5),
CARRYING THE ACTIVATION MARKER CD25.EXPRESSION
OF THE TRANSCRIPTION FACTOR FOXP3 ACTUALLY,
THERE ARE SEVERAL FUNCTIONALLY RELATED
SUBPOPULATIONS Treg, Th3, Tr1 ACT VIA
SUPPRESIVE CYTOKINES (IL-10, TGFb) OR BY
CELL-CELL CONTACT.
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SEVERAL TYPES OF Ts (Tr)CD4(CD25)natural
Treg, induced Tr1 (IL-10), induced Th3
(TGFb)CD8 (HLA-E restricted??)CD4-,CD8-NK-Tg
dT subpopulations
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Biology of Tregs
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How Tregs arise??
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REGULATORY (SUPPRESSOR) T CELLS ARISE IN1)
THYMUS (NATURAL Treg, CD25 SUPPRESS
AUTOIMUNITY) 2) PERIPHERAL TISSUES (INDUCED
Tr1, Th3 DAMPEN IMMUNE REACTIONS TO PATHOGENS)
- PHENOMENON OF
SO CALLED INFECTIOUS TOLERANCE CONVERSION
OF OTHER T CELLS INTO SUPPRESSORS!!
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Development of Treg in thymus
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Thymic development of FoxP3 cells
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The antigen recognition repertoire of Tregs Tregs
are essentially autoreactive T cells recognizing
with relatively high affinity various
MHCgp-peptide complexes they are not eliminated
by negative selection (perhaps because of
involvement of specialized thymic stromal cells?)
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Peripheral generation of Tregs from naïve T cells
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Differentiation of naïve CD4 T cells into Treg
or Teff
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Markers, FOXP3
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FoxP3 controls Treg development and function
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Control of Treg function by FoxP3
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Regulation of physiological immune reactions
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CRITICAL ROLE OF DENDRITIC CELLS DC (MAINLY
IMMATURE?) SUPPORT THE DEVELOPMENT OF REGULATORY
T CELLS.
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Treg activation, proliferation, and
differentiation Activated by contact with DC
(even immature!). Dominant, tonic, default
suppression of potentially self-reactive T
cells. Proliferation after stimulation of TLR2,
4, 5, 8.
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Key role of IL-2 in immune homeostasis
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Trafficking and localization of Tregs Blood,
lymphoid organs variety of homing receptors
necessary for migration to lymph nodes, sites of
inflammation, epithelia.
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INFECTIOUS TOLERANCE
P. Hoek - Vesmír
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Mechanism of infectious tolerance ?
P. Hoek - Vesmír
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Mechanisms of action of Tregs??
Multiple modes of Treg-mediated suppression
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Possible mechanisms of of Treg-mediated
suppression
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Mechanisms of action of Tregs
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Mechanisms of action of Tregs
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SUPPRESSION BY TRYPTOPHAN STARVATION?
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IDO - indoleamine 2,3-dioxygenase
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Do effector T cells potentiate Treg cell
functions?
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How effector T cells may boost Treg activity
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Human CD25Foxp3 Treg cells differentiate into
IL-17-producing cells. When stimulated by
activated DC or monocytes, in the presence of
rhIL-2/rhIL-15. Thus - mature Tregs can be
reprogrammed into competent effector cells!!
Tregs may represent a reservoir of autoimmune
effectors this may be dangerous (autoimmunity)
but also useful (a new approach for breaking
tolerance to self Ags as a strategy for cancer
immunotherapy). J. Immunol. 2008 Sep
1181(5)3137-47 Blood. 2008 Sep
15112(6)2340-52.
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PRACTICAL CONSEQUENCES AND APPLICATIONS?
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Effects of Treg deficiency in mice
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Effects of Treg deficiency in humans
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LOSS OF Treg IN AUTOIMMUNE DISEASESGlobal
Natural Treg Depletion in Active Systemic Lupus
Erythematosus
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HOPEFULLY- BETTER IMMUNOSUPRESSION
(AUTOIMMUNE DISEASES, TRANSPLANTATIONS)
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