Download Immunoregulation How the immune system maintains the delicate

Immunoregulation
How the Immune System Maintains the
Delicate Balance Between Effective Defense
and Auto-immunity?
•
•
•
•
1. To accelerate or to brake?
2. Where to kill?
3. Which cell to kill?
4. How to maintain the diversity in the
arsenal while avoiding self-destruction?
The Growth of Scientific Knowledge
• Karl Popper: The process of
“falsification”
• Thomas Kuhn: "Normal science",
the process of consolidating the
paradigm
The paradigms of immunoregulation
•
•
•
•
1. Network theory
2. Helper-suppressor theory
3. Th1-Th2 theory
4. Activation and inhibition signal
theory
• 5. The return of suppressive T cells
How the immune balance is
achieved?
The Network Theory
• Proposer: Niels Jerne in 1972 (1912-1994,
Nobel prize 1984)
• The immune recognition is based on a
repertoire of antigen receptors reflecting
the outside world. The regulation of
immune reaction is based on the balance
between these antigen receptors.
Niels Jerne: Science as
Autobiography
Darwinian vs.
Lamarckian theory in
Immune responses
Niels Jerne
達爾文的進化論
Survival of the fittest.
物競天擇，適者生存
Niels Jerne: From clonal selection
to immunoregulation
(Idiotype) Network Theory
1. The antigen receptors are extremely
heterogeneous.
2. There are antibodies that recognize the antigen
binding sites (idiotopes) of another antibody.
3. There are potential similarity between Ab2 and
original antigen, Ab1 and Ab3 etc.
4. Balance between these preexisted idiotype antiidiotype antibodies can be disturbed when
outside antigens are introduced into the
immune system.
How the Network Balance Is Achieved
1. Ab2 antibodies held Ab1 production in check.
2. Introduction of antigen will stimulate Ab1 while
suppress Ab2 B cells
3. Asymmetric interactions. There are different
regions in the antibody V regions. Idiotope
and paratope. The idiotope is stimulative
while the paratope is suppressive. (Since the
theory was formulated, however, the network
interaction are generally found to be
symmetric)
Network Balance (I)
Network Balance (II)
How the Network Theory Went Out of
Fashion
• 1. The gene recombination of antigen
receptors was found (S. Tonegawa 1976,
Nobel prize 1987)
• 2. The difficulty in demonstrating idiotype
connections at cellular level
The Helper-suppressor Paradigm
There are CD8+ suppressor
T cell populations that have
antigen specific
suppressive activity and
can be transferred between
animals.
Experimental Evidences
• Adoptive transfer of T cells from mice
tolerant to a given antigen reduces the
immune responses to that same antigen
in syngeneic recepients.
• This antigen specific suppression was
MHC restricted. The gene was mapped to
a region between I-A and I-E termed I-J.
The Proposed Theory of T Suppressors
1. Antigen presentation cells in immune
previlaged sites (such as brain and eyes)
induce tolerance by stimulating T
suppressor cells.
2. T suppressor cells secrete antigen
specific suppressive factor (TCR alphaalpha) and specifically inhibit the immune
responses in these sites.
The Downfall of T Suppressor Theory
1. The I-J was not found after the genomic
sequencing between I-A and I-E was
completed
2. Antigen specific suppressing factors
were not convincingly demonstrated.
3. The uprising of more attractive theories
(T cell tolerance and Th1-Th2 theory)
Th1-Th2 Theory
• In 1986, Mosmann et al. proposed a major
subdivision of mouse CD4+ helper T cells
clones based on their pattern of cytokine
production.
• Th1: IL-2 and IFN-
• Th2: IL-4 and IL-5
• Similar phenotypes have been found in
human T cell clones.
Balance of Th1 and Th2 in Disease States
Studies in mice infected with the protozoan parasite Leishmania major
confirmed the importance of IFN-g and IL-4
C3H mice produce Th1 response and are resistant to the parasite
BALB/c mice produce Th2 response and are susceptible to the
infection
↓
Anti-IFN administered at the time of L. major infection ablates the Th1
response in C3H mice
Anti-IL-4 administered at the time of L. major infection inhibits the Th2
response in BALB/c mice and and establish a protective Th1
population.
Similar phenotypes were observed in human especially in patients with
allergy (Th2) or intracellular infection (Th1)
Observations to Confirm/falsify the
Th1-th2 Theory
• Leprosy: Patients with lepromatous
leprosy have Th2 dominant states while
patients with tuberculoid leprosy have
Th1 dominant states.
• Allergy: Patients with Th2 dominant
states tends to have IgE mediated allergy
( Science 1997, 275:77)
Th1 Response
and Asthma
Th1-Th2 balance
The return of suppressive T cells:
TR TS cells
After being dormant for more than a
decade, the T cells that bear specific
antigen receptors and are active in
suppressive functions are back…
Featuring new cast, new makeup, new
tricks, and more.
The third warrior: regulatory T cells
The return of suppressorregulatory T cells
• The evidence thickened for active,
transferable, antigen specific, suppressive T
cell activity.
• Autoimmunity was observed at an
unexpected high frequency in some
manipulated animals:
a. thymectomized mice
b. cytokine or cytokine receptor gene
knockout mice (e.g. IL-2, IL-2Rb knockout)
Relevant knowledge
development in the last decade
regarding regulatory T cells
• Many suppressive cell surface molecules and
intracellular signaling pathways in leukocytes
were found.
• Cell trafficking as a mode a
immunoregulation was established.
• Enthusiasm for Anergy as a pathway of
antigen-specific tolerance induction has
peaked than subsided.
The cell-transfer models for
autoimmunity
• SCID recipients with CD4+ CD45RB hi T
cells from normal mice develop
autoimmune colitis and other autoimmune
diseases including psoriasis.
• Cotransfer of CD4+ CD45RB lo population
inhibits disease development.
The new face of regulatory T cells
• Transferring subpopulation of T
lymphocytes leads to autoimmunity
CD5+
CD45RB low or intermediate
CD62L+
CD25+
…
Anergy and regulatory T cells
• Anergy caused by lack of costimulation
has been seen as a potential
mechanism for antigen specific
tolerance.
• Anergic cells do not produce IL-2 and
anergy is broken by exogenous IL-2.
• Anergy should be non-transferrable
• TR cells express may phenotypes of
anergic T cells.
Anergic/regulatory T cells (continued)
• Some anergic T cell clones can
suppress immune responses in vivo.
• TR cells do not produce IL-2
• Allogeneic stimulation of human CD4 T
cells in vitro in the presence of IL-10
induces T cell anergy. A T population
that produces IL-10 and TGF-b then
emerges.
Antigen recognition appears
essential for these cells
• Presence of target antigens in the
animals is essential for the induction
and maintenance of TR cells.
• Positive /negative selection for these
cells appears similar to “traditional” T
cells.
Control of immune pathology by TR cells
Two potential mechanism for the
TR cell mediated suppression
Potential mechanisms for the TR
cell mediated suppression
A multiple-dimensional immuno-homeostasis
Future directions
• How TR cells affect other T cells?
• Trafficking of T cell subpopulations and APCs
in the induction and maintenance of
regulatory T cells
• Role of antigen specificity in the
determination of Th/TR cells (epitope vs.
paratope?)
• The role of regulatory cells in human
diseases e.g. Wiskott Aldrich syndrome
The Saint Grail:
Immunomodulation
• Immunoregulation is not an all-or-none switch.
• The refurbishment of immunoregulation theories
leads us to levels of better understanding in
leukocyte biology.
• The next paradigm shift: to come to laboratories
near you soon.