How is the immune response turned off after it is activated?
Once the immune response has been activated, it is important to restore immune homeostasis. This is done through various mechanisms:
• Negative regulation of the innate immune response.
• Efferocytosis: activation of macrophages induces not only the secretion of proinflammatory molecules but also antiinflammatory mediators (IL-10, TGF-β, and PGE 2 ) that downregulate macrophage and DC function. Macrophage ingestion of apoptotic cells (efferocytosis) that they identify by phosphatidylserine on the apoptotic cell’s outer surface results in the release of antiinflammatory mediators.
• Negative regulation of the adaptive cellular immune response.
• CTL-associated protein (CTLA-4): after activation, T cells increase the expression of CTLA-4, which has higher affinity for CD80/CD86 than for CD28 leading to loss of costimulation. This results in cessation of T-cell proliferation and cytokine production.
• Activation-induced cell death: the signals that activate T cells also result in upregulation of Fas and TNFR on their surface. When Fas binds to FasL on another cell, soluble TNFα binds to TNFR1, or transmembrane TNFα binds to TNFR2, the activated T cell undergoes apoptosis.
• Treg suppression: Tregs release IL-10 and TGF-β, which suppress the immune response. Other suppressor T cells also exist (Tr1, Th3, CD8+CD28+).
• Breg suppression: Bregs (B10) release IL-10, which suppress T cells and DCs. Other subsets of Bregs exist.
• Negative regulation of the adaptive humoral immune response:
• IgG binds antigen and eliminates it, so it no longer serves as an inducer of the immune response.
• IgG binds antigen-forming immune complexes. These immune complexes can bind to FcγRII on B cells which suppresses them.
• Antiidiotype antibodies may neutralize antibody being made by binding to its idiotypic determinants.
• Regulation of complement cascade: C1 inhibitor, C1INH, binds C1r/C1s preventing C1 activation. C3 convertase (C4b2a and C3bBb) and C5 convertase (C4b2a3b and C3bBbC3b) are regulated by serum inhibitors (C4-binding protein and factor H) and membrane-bound factors (decay accelerating factor [DAF] and membrane cofactor protein [MCP]). C4b-binding protein inactivates C4b and the classical pathway, and factor H inactivates C3b and the alternative pathway by serving as cofactors for factor I-mediated cleavage of C4b and C3b, respectively. DAF causes release of C2a or Bb from cell surfaces leaving C4b and C3b to bind to MCP, which serves as a cofactor for factor I-mediated cleavage of C4b/C3b, halting the classical and alternative complement cascades. Complete deficiency and loss of function polymorphisms of factors H and I result in dysregulated complement activation and the atypical hemolytic uremic syndrome. Other complement regulatory proteins (vitronectin, CD59) block fluid phase and membrane-bound MAC. Note that all these regulatory proteins bind to glycosaminoglycans specific to host cells and not on microbes, therefore protecting host cells while allowing complement-mediated destruction of pathogens.