MBI - 414 Immunology Principles
MBI - 415 Immunology Principles and Practice

Cytokines

• Cytokines act much like hormones, and their actions are classified according to the distance from the secreting cell to the "target" cell
  • autocrine - cytokines can act on the cell that secreted them (the secreting cell is the "target" cell)
  • paracrine - cytokines can act on nearby cells (as opposed to the cell that secreted them)
  • endocrine - cytokines can act on cells that are located far away, and they typically use the circulatory system to travel to their "target" cells
• Cytokines can act on many targets, can act in concert, or can antagonize one another
  • pleiotropy - cytokines can act in a similar way on more than one "target" cell ... e.g., IL-4 can stimulate proliferation in T cells, B cells or mast cells
  • redundancy - more than one cytokine can trigger identical or similar responses in a given "target" cell ... e.g., IL-2, IL-4, and IL-5 can all induce B cell proliferation
  • synergy - cytokines can act together to induce a different response than either of them can induce by itself ... e.g., IFN-γ and TNF-α induce IDO much better than IFN-γ alone (and TNF-α does not induce IDO by itself)
  • antagonism - cytokines can counteract one another ... e.g., IFN-gamma blocks the isotype switch to IgE that is normally induced by IL-4
  • cascade induction - cytokines can act in sequence (much like an enzymatic pathway) ... e.g., macrophages secrete IL-12 when stimulated by LPS; IL-12 induces IFN-gamma secretion by T helper cells; IFN-gamma activates macrophages
• Cytokine families
• hematopoietin family - includes IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11, IL-12, IL-13, IL-15, IL-21, IL-23, IL-27, GM-CSF, G-CSF, OSM , LIF, CNTF, GH, prolactin
• interferon family - includes IFN-α, IFN-β, IFN-γ and cytokines such as IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, IL-29
• TNF family - includes TNF-α, TNF-β, CD27L, CD30L, CD40L NGF, FAS
• chemokine family - includes
• Cytokine receptors
  • immunoglobulin superfamily receptors
    • characterized by the presence of one or more Ig folds
    • bind cytokines such as IL-1, M-CSF, c-Kit, IL-18
  • hematopoietin (class I cytokine) receptors
    • characterized by a sequence including four positionally conserved cysteines (CCCC motif) in their membrane distal domain and a WSXWS sequence in their membrane proximal domain
    • bind hematopoietin cytokines such as IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11, IL-12, IL-13, IL-15, IL-21, IL-23, IL-27, GM-CSF, G-CSF, OSM , LIF, CNTF, GH, prolactin
  • interferon (class II cytokine) receptors
    • characterized by a sequence including four positionally conserved cysteines (CCCC motif) in both their membrane distal domain and their membrane proximal domain
    • bind interferons (IFN-α, IFN-β, IFN-γ) and cytokines such as IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, IL-29
  • TNF receptors
    • characterized by a sequence including six positionally conserved cysteines (C2-C3-C1 motif) in every extracellular domain
    • bind TNF family cytokines such as TNF-α, TNF-β, CD27L, CD30L, CD40L NGF, FAS
  • Chemokine receptors
    • characterized by multiple transmembrane regions in association with G proteins:
      • CC subgroup (conserved pairs of juxtaposed cystines) - CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10
      • CXC subgroup (conserved pairs of cystines separated by another amino acid) - CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6
    • bind all the chemokines
      • CC subgroup ... e.g., CCR1 binds MIP-alpha; CCR2 binds MCP-1
      • CXC subgroup ... e.g., CXCR1 and CXCR2 bind IL-8; CXCR3 binds IL-10