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
- Slides: 54