Immunity and tolerance Susanne Brix Pedersen Assistant Professor

Immunity and tolerance Susanne Brix Pedersen, Assistant Professor Nutritional Immunology Group CBS, Bio. Centrum-DTU

The central issue: immunity versus tolerance The immune system has the tremendous task to eliminate pathogens and eradicate arising tumours, while preventing auto-reactive responses that are harmful to the host. In keeping with balancing this dual task, a complex interplay between immune cells exists and many stimulatory and inhibitory circuits are in place. Deregulation of this intricate balance is directly associated with human diseases, ranging from inflammatory and autoimmune disorders to infection and cancer.

Definitions Immunity: Effective clearance of all infectious agents and tumours by immune cells Tolerance: Hindering of autoimmunity, and down-regulation of immune responses after clearing of pathogens

Discrimination between “self” and “non-self” Every immune response depends on regulation at the single-cell level

Immune regulation Christensen, HR (2003)

The balance between effector cells is essential for immune regulation

Different lines of tolerance induction Regulation of tolerance is two-legged: 1) Central regulation marrow) 2) Peripheral regulation (thymus, bone

Central T cell tolerance Ideally, selected T cells contain TCRs with low affinity for self MHC in combination with “non-self” antigens, but usually auto-reactive T cells also exists in the periphery

Peripheral tolerance Ways of down-regulating immune responses in the periphery: Ø Anergy – no co-stimulatory signal Ø Deletion - by apoptosis Ø Active suppression (by naturally-arising or peripherally induced Tregs)

Peripheral tolerance: anergy (non-responsiveness) + Co-stimulation No co-stimulation

Peripheral tolerance: apoptosis (programmed cell death)

Central generation of Tregs: The naturally-arising Tregs

Peripherally-induced Tregs

Different Treg populations Akbar et al. Nature Reviews Immunology 7, 231– 237 (March 2007) | doi: 10. 1038/nri 2037

Treg-mediated suppression: In case of auto-reactive T cell clones

Treg-mediated suppression: during down-regulation of responses to pathogens

Turning to productive immunity + Tregs

Immunity: Important parameters Sensing of “Danger” signals by APCs Antigen uptake and presentation pathway Signal strength (APC-CD 4+ T cell interaction) Cytokine pattern Surface molecule expression

Antigen-presenting cells

The antigen carries the signal

Immunity: Important parameters Sensing of “Danger” signals by APCs Antigen uptake and presentation pathway Signal strength (APC-CD 4+ T cell interaction) Cytokine pattern Surface molecule expression

Immature DCs takes up antigen Antigen processing pathways

Antigen presentation pathways

Mature DCs activates naïve CD 4+ T cells

Immunity: Important parameters Sensing of “Danger” signals by APCs Antigen uptake and presentation pathway Signal strength (APC-CD 4+ T cell interaction) Cytokine pattern Surface molecule expression

Central regulation (thymus) Activation of naïve T cells requires at least moderate signals i. DCs induces weak signals, leading to anergy Activation of B cells requires strong signals Killing by CTLs requires strong signals

Immunity: Important parameters Sensing of “Danger” signals by APCs Antigen uptake and presentation pathway Signal strength (APC-CD 4+ T cell interaction) Cytokine pattern Surface molecule expression

Cytokines are important polarizing agents Zeuthen, LH (2006)

Immunity: Important parameters Sensing of “Danger” signals by APCs Antigen uptake and presentation pathway Signal strength (APC-CD 4+ T cell interaction) Cytokine pattern Surface molecule expression

Activation of CD 4+ T cells requires formation of the immunological synapse

Activation or inhibition? Importance of co-stimulatory signals and cytokines

Co-stimulatory ligands determine the CD 4+ T cell fate

Activation of CD 4+ T cells

Timing in T cell activation

Induction of immunity Importance of CD 4+ T cells: CD 4+ T cells are central in providing help for CD 8+ T cell and B cell activation

Th 1/Th 2 cells in immune activation Christensen, HR (2003)

Activation of CD 8+ T cells

Killing of virus-infected cells Apoptosis is induced due to the action of perforin (making pores), and the granule-containing granzyme B, a serine protease which activates a variety of caspases.

CTLs in virus clearance

Activation of B cells

Activation of B cells – antibody secretion

Effector responses to virus

Summing-up: Immunity and tolerance

Deregulation to endogenous challenges Deregulation of the immune response can lead to several pathological reactions e. g. : Ø Autoimmune diseases Ø Allergy Ø Cancer

Initiation of autoimmune diseases Sequestering of self-antigen into bloodstream – e. g. by insult. Altering of body substance for example, by virus, drug, sunlight, or radiation. The altered substance may appear foreign to the immune system. For example, a virus can infect and thus alter cells in the body. The virus-infected cells stimulate the immune system to attack. Molecular mimicry - A foreign substance that resembles a natural body substance may enter the body. Targeting of the similar body substance as well as the foreign substance. Malfunctioning of B cells, resulting in production of self-reactive antibodies.

Autoimmune diseases in humans

Autoimmune reactions

Type I Ig. E-mediated allergic response Allergen: pollen, fur, food etc.

Type I Ig. E-mediated allergic response

Typical cytokine profiles in allergy

Treg suppression of Th 2 response Allergy vaccination strategy

Induction of Tregs by cancer cells Cancer cells are able to shed of immunosuppressive components e. g. gangliosides Zou Nature Reviews Immunology 6, 295– 307 (April 2006) | doi: 10. 1038/nri 1806