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 ( , 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 Niels Jerne: Science as Autobiography Darwinian vs. Lamarckian theory in Immune responses

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 anti- idiotype 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 alpha- alpha) 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: T R T S 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 suppressor- regulatory 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-2R  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 T R cells express may phenotypes of anergic T cells.

Anergic/regulatory T cells (continued) Some anergic T cell clones can suppress immune responses in vivo. T R 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-  then emerges.

Antigen recognition appears essential for these cells Presence of target antigens in the animals is essential for the induction and maintenance of T R cells. Positive /negative selection for these cells appears similar to “traditional” T cells.

Control of immune pathology by T R 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 T R 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/T R 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.