Integrated dynamics of innate and adaptive immunity

• Describe stage 1: barrier breach of the immune response

  In this stage, a body barrier surface is breached by a pathogen and local infection is established. In order for this to occur, an invader must be able to adhere, penetrate or colonise the tissue it has invaded and replicate within the environment. This infection results in the release of PAMPs and DAMPS.
• Describe stage 2: activation of innate immunity in the immune response

  Infection results in changes in the local environment, which activates cells in the innate immune system, e.g., tissue resident macrophages and dendritic cells. These cells produce cytokines and chemokines, which recruit and activate ILCs to secrete cytokines and chemokines. Innate immune cells also activate endothelial cells, which express integrins to recruit circulating innate immune cells. This response is largely non-specific and rapid in nature, but it can be sustained for several days in order to control pathogens.
• Describe stage 3: lymphatic spread of the immune response

  In this stage infection eludes the local innate responses or the antigen threshold is met, which results in penetration of the epithelium and local infection of tissues. Antigen bearing dendritic cells and free antigen then drain from the site of infection to local lymph nodes, resulting in activation of antigen specific B and T cells. These lymphocytes expand and differentiate over a few days, before T cells and antI body are released from the lymph node and enter the infected tissue.
• Describe stage 4: adaptive immune response

  Antigen specific T cells and antibodies enter the site of infection and produce a more potent response than earlier stages due to the precise targeting of pathogen.
• What is an effector immune module?

  Type of infection determines the immune effector module that is activated and each module defines a specific immune population of cells, e.g., ILCs, effector T cells, antibody isotypes.
• Describe the different effector immune modules

  Type 1: ILC1 helps coordinate the activation of Th1 cells, IgG1 and IgG2, which potentials the activation of macrophages and monocytes.

  Type 2: ILC2 coordinates the activation of Th2 cells and IgE, which potentials the activation of eosinophils, mast cells and macrophages.

  Type 3: ILC3 coordinates the activation of Th17 cells and opsonising IgG, which potentiates the activation of neutrophils.
• How do activated T cells reach the site of infection?

  Molecules on the T cell surface are altered following activation:

  • Naive T cell: express CCR7, which promotes trafficking to the lymph nodes
  • Activated T cell: express P-selection glycoprotein ligand 1, which binds P and E selectins on activated endothelium. Also express sphingosine 1-phosphate receptor 1, which binds to S1P and facilitates trafficking out of the lymph node.
• Describe T cell subset specific expression of chemokine molecules

  There are distinct patterns of chemokine receptor on T cell subsets, which permits differential recruitment to sites of inflammation depending on the chemokines expressed:

  • Th1: express CXCR3 and CCR5. Reflects expression of the innate cells they recruit, e.g., monocytes express CCR5
  • Th2: CRTH2 and CCR4
  • Th17: CCR6

  Shared expression of chemokine receptor by innate and adaptive cells allow spatial and temporal coordination of immune response.
• What do Th1 cells do once at the infection site?

  Once at the site of infection, Th1 cells promote classical activation of macrophages, which requires production of IFN-gamma and CD40L. This results in the formation of M1 macrophages, which exhibit enhanced abilities to kill intracellular pathogens. Th1 cells also secrete Il-3 and GM-CSF, which stimulates monocyte production in the bone marrow. As well as, secreting TNF-alpha and lymphotoxin, which alters the surface properties of endothelial cells to permit monocyte adherence. Th1 cells induce CCl2 expression to directly recruit monocytes.
• Describe action of M1 macrophages

  These cells exhibit enhanced abilities to kill intracellular pathogens, but they also express increased levels of; MHC, CD80/86, and CD40. This allows them to provide both signal 1 and 2 to T cells. They can also secrete IL-12, which acts on ILCs and Th1 cells to promote IFN-gamma production. IL-12 also promotes stabilisation of Th1 cells and differentiation of CD8+ T cells to CTLs.
• What do Th2 cells act to expel worm infection?

  • Produce IL-5 to recruit and activate eosinophils, which produce myelin basic protein to kill parasites.
  • Produce IL-3 and IL-9 to recruit mast cells, which secrete histamine, TNF-alpha, and MMCP to recruit inflammatory cell and remodel the mucosa.
  • Produce IL-13 to induce epithelial cell repair and mucus, which increases cell turnover to shed parasitised epithelial cells. Also increases smooth muscle contractility that enhances worm expulsion.
• How do Th2 cells act to promote wound healing?

  Th2 cells limit tissue damage and promote wound healing at the site of infection:

  • Secrete IL-4 and IL-13 to promote alternative activation of macrophages
  • M2 macrophages can promote worm expulsion as well as tissue remodelling repair by expressing the enzyme arginase I, which catalyses the breakdown of arginine to ornithine, which promotes tissue remodelling and repair
• What do Th17 cells do at the site of infection?Th17 cells are important for the recruitment of neutrophils:

  • Secrete IL-17, which activates stromal and myeloid cells to produce G-CSF to stimulate neutrophil production in bone marrow
  • Produce IL-22 which drives epithelial cell production of Antimicrobial peptides of peptides including: RegIII-beta and gamma (directly kill bacteria) and S100A8 and S100A9 (sequester zinc and manganese from bacteria)
  • IL-22 also drives epithelial cell proliferation to shed cells and prevent colonisation by pathogen
• What happens once the infection is resolved?

  • Antigens that initiated response are removed
  • Most effector T cells undergo death by neglect:
  • Cells die via apoptosis due to loss of survival factors, e.g., IL-2
  • Apoptotic lymphocytes are cleaved by phagocytes
  • Recognise phosphatidylserine on the outer surface