Lecture 6 - Adaptive Immunity (immune cell migration)

• Leukocyte extravasation


  1. Rolling

  2. Activation

  3. Firm adhesion

  4. Transmigration
• Rolling


  Naive T cells express L-selectin, which binds to glycoproteins on high endothelial venules (HEV), leading to transient and weak interactions that cause immune cell rolling due to shear force of blood flow
• Activation


  Chemokines convert rolling to firm adhesion by displaying CCL19 and CCL21 on HEV, which binds to CCR7 receptor on naive T cells, leading to signaling and integrin activation
• Firm adhesion


  Chemokines cause integrins to undergo conformational shift, leading to conversion to high affinity ICAM1 binding and firm adhesion of T cells to endothelial cells of HEV
• Transmigration


  Naive T cells produce metalloproteases to transit between endothelial cells and through the basement membrane, allowing them to enter lymph node
• Chemokines

  • Secreted molecules that bind to cell surface GAGs and ECM proteins, forming immobilised concentration gradients
  • Target cells express chemokine receptors, which are coupled to heterotrimeric G proteins, leading to signaling and activation of integrins
• Integrins


  • Heterodimeric proteins that bind to members of immunoglobulin superfamily, such as ICAM1 on endothelial cells, leading to firm adhesion of immune cells
• Chemokines and adhesion molecules play a crucial role in the different steps of leukocyte extravasation, including rolling, activation, firm adhesion and transmigration
• Types of chemokines

  • Homeostatic
  • Inflammatory
• Homeostatic chemokines


  Involved in immune cell homing to target organs in absence of inflammation
• Inflammatory chemokines

  Induced by infection or inflammation, recruit immune cells to sites of inflammation by activating integrins and promoting firm adhesion and migration
• The interaction between chemokines, adhesion molecules and immune cells is essential for the movement of immune cells from blood into lymph nodes and peripheral tissues, as well as their exit from lymph nodes
• Homeostatic chemokines, such as CCL19 and CCL21, are constitutively expressed to attract CCR7+ naive T cells and dendritic cells to T cell area of lymph nodes
• The T cell zone contains specialised fibroblasts (fibroblastic reticular cells; FRCs) that produce CCL19 and CCL21, creating a gradient that attracts CCR7+ naive T cells and dendtritic cells to the T cell area
• Tissue dendritic cells upregulate CCR7 in response to pathogen associated molecular patterns (PAMPS) or inflammatory cytokines, further contributing to the recruitment of immune cells to lymph nodes
• Chemokine signaling leads to integrin activation, specifically integrin LFA1 expressed by naive T cells, which is crucial for firm adhesion to the endothelial cells in high endothelial venules (HEV)
• Chemokines also cause inside-out signaling, resulting in a conformational shift in surface integrins and conversion to high affinity ICAM1 binding, facilitating firm adhesion and migration of immune cells
• Naive T cells produce metalloproteases to transit between endothelial cells and through the basement membrane, ultimately leading to transmigration and entry into the lymph node
• Different infections induce different "chemokine signatures" and require different types of immune responses
• Viral infections induce interferon gamma production, which stimulates macrophages to make CXCL9/10/11
• CXCL9/10/11 bind to CXCR3 to recruit anti-viral T cells
• Parasitic worm infections induce interleukin-13 (IL-13) production, which stimulates macrophages to make eotaxins (CCL11 , CCL24, CCL26)
• Eotaxins bind to CCR3 to recruit anti-parasite eosinophils
• Chemokines play a crucial role in recruiting immune cells to sites of inflammation and infection