Activation of Effector Cells

Activation of Effector Cells

  • Multiple effector mechanisms ensuring the elimination of invaded pathogen include cell recruitment to inflammatory focus, stimulation of phagocytosis and antigenic presentation, cytotoxic action of T killers and NK cells, conversion of B cells into plasma cells with the secretion of antibodies of various Ig classes.
  • The reactions of specific adaptive immunity are also followed by the clonal expansion of activated immune cells, which leads to the increase of a number of antigen-specific cells reacting against the pathogen.
  • When differentiated, Th1 produce γ-interferon that activates macrophages and dendritic cells.
  • They greatly enhance the production of pro-inflammatory cytokines IL-1, IL-12, IL-18, alpha-TNF thus augmenting further Th0 differentiation into Th1.
  • Furthermore, these cytokines arrest Th2 maturation. Progression of cell-mediated reactions results in delayed-type of hypersensitivity with granulomatous inflammation.
  • And vice versa, Th2 cells produce a broad spectrum of interleukins (IL-4, IL-5, IL-10, IL-13). Activation by IL-4 and costimulation of B cells via CD40L of Th2 triggers blast transformation of B lymphocytes into plasma cells.
  • This results in antibody affinity maturation and secretion (humoral immune response). Newly generated highly specific Abs neutralize Ags or opsonize Ags for phagocytes, activate the complement pathways thereby eliminating invaded pathogens.
  • Additional T helper populations also intensively stimulate effector immune reactions.
  • For instance, activated Th17 start to produce IL-17, IL-21, and IL-22 cytokines. This leads to the activation of multiple lines of immune and non-immune cells (T cells, neutrophils, macrophages, NK cells, B cells, epithelial and endothelial cells), resulting in progressive chronic inflammation, enhancement of phagocytosis and antibody synthesis, maturation of myeloid cells, and in some cases, generation of an autoimmune response.
  • Activated follicular T helper cells stimulate the transformation of follicular B lymphocytes into long-living antibody-secreting plasma cells and memory B cells.
  • In case of the immune response against viruses, intracellular bacteria (chlamydia, rickettsiae, etc.) or tumour cells another type of Ag elimination occurs.
  • In these situations, antigen-specific cytotoxic T cells (or Tc) become activated.

Activation of Effector Cells

Mechanisms of immune cytolysis by Tc cells include:

  1. target cell recognition and activation of Tc lymphocytes via HLA I-Ag complex expressed by infected or malignant cell;
  2. secretion of killing molecules by Tc cells with subsequent target cell elimination.
  • Literally all nucleated cells are capable of presenting Ag for T-cytotoxic cells (Tc or T killers). When infected, the cell expresses antigenic peptides of invaded pathogens in complex with HLA I class molecules (HLA-A, HLA-B, or HLA-C) upon its cytoplasmic membrane.
  • Complex “Ag-HLA I” is recognized by cytotoxic Tc bearing specific TCRs. This binding is supported by CD8 and CD3 molecules. Activation of Tc needs also additional costimulatory molecules and cytokine stimulation (mainly, γ-interferon and IL-2 from Th1). Once activated, Tcs render Ag-specific cytotoxic activity against infected or tumour cells.
  • Activated (CD8+) T cells (T killers) release a vast number of cytotoxic factors that eventually cause target cell death. Among them are effector proteins perforin, granzymes, and granulysin.
  • For instance, perforin is highly active cytotoxic protein demonstrating lytic activity similar to membrane attacking complex of complement. Perforin acts as pore-forming toxin allowing granzymes to enter the infected cell and stimulate apoptosis via activation of caspases.
  • In addition, Tcs stimulate apoptosis by elevated expression of FasL that binds to apoptosis receptor CD95 Fas/Apo upon the membranes of target cells.
  • Finally, Tcs activate the secretion of γ-interferon that arrests viral replication and stimulates the antiviral and anti-tumour activity of NK cells.
  • Likewise, a great variety of cytotoxic substances is produced by natural killers or NK cells. When stimulated by signals from their inhibitory or activation receptors, they destroy the target cells by secretion of perforin, granzymes or lymphotoxins.