T cell Effector Mechanisms

Cell-Mediated Immunity Refresher

  • Cell-mediated immunity involves effector T cells that eliminate microbes.
  • The immune system has different types of immune cells to combat various pathogens, which differ in size, infect different body sites (intracellular vs. extracellular), have different life cycles, and have diverse mechanisms of pathogenesis.
  • Innate and adaptive immune systems are integrated, with effector modules tailored to different pathogens:
    • Cytotoxicity: targets cytosolic pathogens and tumor cells.
    • Type 1 immunity: targets intracellular (vesicular) pathogens.
    • Type 2 immunity: targets macroscopic pathogens like helminths.
    • Type 3 immunity: targets extracellular pathogens.
  • DCs capture antigens in the periphery, then migrate to the lymph nodes (LN) and localize in the T cell zone.
  • DCs express peptide:MHC and costimulatory molecules.
  • Naive T cells enter the LN from the circulation and localize to the T cell zone.
  • Naive T cells recognize peptide:MHC on DCs, initiating the T cell response.
  • T cell activation requires:
    *Signal 1: antigen recognition (TCR recognition of peptide:MHC).
    *Signal 2: costimulatory signal (CD28 interacting with B7 on activated APCs).
    *Signal 3: cytokines, which are crucial for the differentiation of helper T cell subsets.
  • Following activation, naive T cells undergo clonal expansion and differentiate into effector cells.
  • Effector T cells leave the LN and migrate to the site of infection via the circulation.
  • At the infection site, effector T cells are reactivated and act to eliminate pathogens.
  • Activated T cells differentiate into the most appropriate effector T cell subset for the elimination of a particular microbe.
    • Cytosolic microbes are presented on MHC class I, recognized by cytotoxic T cells (CTLs), which then kill the infected cells.
    • Intracellular (vesicular) and extracellular microbes are presented on MHC class II, recognized by helper T cells, leading to activation of macrophages and B cells; also causing inflammation and activation of neutrophils, mast cells, and eosinophils, and antibody production.
  • Naive and activated T cell migration:
    • Naive T cells use L-selectin, CCR7, and LFA-1 to enter the lymph node.
    • Activated T cells use E/P-selectin ligands, CXCR3, and LFA-1 or VLA-4 to enter peripheral tissues.

Helper T Cell Subsets: Th1, Th2, and Th17

  • Cytokines drive the differentiation of helper T cell subsets. Other leukocytes can also provide these cytokines for differentiation.
  • Cytokines in the local environment ensure the development of the most appropriate helper T cell subset for a particular microbe.
  • These cytokines induce the activation of specific transcription factors which determine the differentiation of helper T cell subsets.
  • Different helper T cell subsets produce different cytokines.
    • Also induced or peripheral regulatory T cells (iTregs or pTregs)
  • Th1 cells
    • Important for intracellular microbes like Mycobacterium tuberculosis and Leishmania.
    • Experimental evidence that Th1 cells are important for intracellular microbes using Listeria monocytogenes:
      • Mouse 1: sub-lethal dose of Listeria monocytogenes
      • Serum harvested and injected into naïve mouse #1. The mouse is susceptible.
      • T cells harvested and injected into naïve mouse #2. The mouse is resistant.
      • Antibodies are ineffective at combatting L. monocytogenes.
      • Activated macrophages do the killing.
    • Effector Functions:
      • Th1 cells secrete IFNγ.
      • IFNγ activates macrophages to become excellent killers of ingested microbes.
      • Helps B cells to make IgG which is beneficial for complement activation, opsonisation and phagocytosis.
      • Drives more Th1 differentiation.
      • T follicular helper (Tfh) cells are the major source of IFNγ.
    • Th1 cells activate macrophages through a combination of IFNγ and CD40/CD40L interactions.
      • Activated macrophages produce ROS, NO, and lysosomal enzymes, enhancing the killing of ingested microbes.
      • Secrete cytokines and chemokines, increasing inflammation and Th1 differentiation.
      • Increased expression of peptide:MHC and B7 molecules increases T cell activation.
  • Th2 cells
    • Important for macroscopic organisms like helminths (e.g., hookworm, tape worm, and Schistosoma).
    • Effector functions:
      • Th2 cells secrete IL-4, IL-5 and IL-13.
      • IL-4 (and IL-13) helps with antibody production by B cells – primarily class switching to IgE.
      • IL-5 activates eosinophils.
      • IL-4 and IL-13 together promote mucus secretion and peristalsis and alternatively activate macrophages.
    • Eosinophils, mast cells and IgE act to eliminate helminths through degranulation.
      • IgE binds to antigens on helminths and is bound by Fc receptors (FcεRs) on mast cells.
      • Multivalent antigen crosslinks IgE bound to FcεR leading to mast cell degranulation.
      • IL-5 from Th2 cells results in eosinophil activation and degranulation.
      • Granules from mast cells and eosinophils are toxic to helminths.
  • Th17 cells
    • Important for extracellular microbes like Staphylococcus aureus, Klebsiella pneumoniae, and Candida albicans.
    • Effector functions:
      • Th17 cells secrete IL-17 and IL-22.
      • IL-17 induces cells to secrete pro-inflammatory cytokines and chemokines, promoting inflammation, attracting neutrophils and monocytes to the site of infection.
      • IL-22 acts on epithelial cells, enhancing the integrity of epithelial barriers.
      • Both IL-17 and IL-22 promote the production of antimicrobial peptides such as defensins.

Regulation and Balance in Helper T Cell Responses

  • There is a balance between Th1 and Th2 responses; the stronger the Th1 response, the weaker the Th2 response, and vice versa.
  • Polarisation of helper T cell response towards a particular subset.
  • Th1 and Th2 cytokines inhibit each other at the developmental level.
    • Th2 cytokines inhibit Th1 differentiation, and Th1 cytokines inhibit Th2 differentiation.
  • Th1 and Th2 response regulation can also happen at the effector level.
  • Two ways to activate macrophages:
    • Th1 cells are involved classical activation of macrophages (M1) which is pro-inflammatory and important in elimination of phagocytosed microbes.
    • Th2 cells alternatively activate macrophages (M2) which is anti-inflammatory and important for wound healing and fibrosis.
    • The Th2 cytokines IL-4 and IL-13 inhibit M1 macrophage activation.
  • The predominant Th1/Th2 response determines disease outcome.
    • Th1/Th2 balance is influenced by both genetics and environmental factors.
    • An ineffective Th cell response results in a quite different disease outcome.
      • Intracellular infections: such as Leishmania or Listeria in laboratory mice.
        • BALB/c mice: Strong Th2 response, susceptible to Leishmania and Listeria.
        • C57Bl/6 mice: Strong Th1 response, resistant to Leishmania and Listeria.
      • Leprosy, caused by Mycobacterium leprae:
        • Tuberculoid leprosy: Granulomas and skin lesions, bacterial counts are low, strong Th1 responses.
        • Lepromatous leprosy: Destructive lesions and disseminated infection, high bacterial counts, weak Th1 responses, strong Th2 and antibody responses.
  • Regulatory T cells also help to control Th1 and Th2 responses.
  • Treg cells suppress the differentiation and proliferation of Th1 and Th2 cells.
  • IL-4 acts to inhibit differentiation of Tμ1 cells.
  • IL-4 or IFN-γ can inhibit development of Tμ17 cells.
  • IFN-γ acts on TH2 cells to inhibit proliferation.
  • Th1 and Th2 cytokines inhibit Th17 differentiation.

Cytotoxic T Lymphocytes (CTLs)

  • CTLs are important for cytosolic microbes and tumors.
  • Only one type of effector CD8+ T cell is known as CTLs.
  • Naive CD8+ T cells may require CD4+ T cell help (such as Th1 cells) for activation and differentiation into CTLs.
    • IL-2 for proliferation.
    • Induces increased costimulatory molecule expression on APCs.
  • Effector function 1:
    • Perforin and granzymes are the effector molecules and are contained within CTL granules.
    • CTLs become activated following recognition of peptide:MHC class I on the infected (target) cell.
    • An immune synapse forms to ensure controlled, directed release of granules to target cell only.
    • Perforin allows granzymes to enter cytosol of target cell – forms “pores” in the cell membrane and vesicle membrane.
    • Granzyme B enters cytosol and activates caspases leading to apoptosis of target cell.
  • Effector function 2:
    • CTLs can also secrete IFNγ.
    • Enhanced anti-viral responses.
    •  MHC class I expression on infected cells and inhibit viral replication.
    • Co-operation in responses to intracellular microbes.
    •  Macrophage activation and  Th1 cell differentiation.

Co-operation Between the Innate and Adaptive Immune Systems

  • The innate and adaptive immune systems are integrated.
  • Immune effector modules are tailored for different types of pathogens.
  • Helper T cells use innate immune cells to mediate effector functions.
  • Th1 cells and CTLs co-operate to eliminate intracellular microbes.
    • Sometimes Th1 cells alone are not sufficient to eliminate intracellular microbes, especially if they can escape into the cytosol….
    • Th1 cells (and CTLs) activate macrophages to kill ingested microbes through secretion of IFNγ.
    • CTLs can also kill infected macrophages.
    • Both are important for complete elimination of these microbes.
  • CTLs, antibodies and Th1 cells co-operate in viral infections.
    • Antibodies neutralise viruses, preventing entry into cells.
    • CTLs kill virally infected cells.
    • Th1 cells: Help with CTL activation and differentiation and help B cells produce neutralising Ab.

Helper T Cells and Disease

  • Th1 cells can cause pathology.
    • Chronic inflammation: Constant activation of M1 macrophages  pro-inflammatory cytokines.
      • E.g. Granuloma formation in tuberculosis – a persistent response to M. tuberculosis.
      • E.g. Inflammatory bowel disease – an unwanted response to commensal bacteria in the gut.
    • Autoimmune diseases: Chronic inflammation may contribute to pathogenesis of some autoimmune diseases where Th cells, CTLs, B cells and macrophages play a role.
      • E.g. Type 1 diabetes, multiple sclerosis
  • Th2 cells can cause allergic diseases.
    • Examples include asthma, allergic rhinitis and anaphylaxis.
    • Exposure to allergen leads to the induction of Th2 cells and the production of IgE.
    • The allergen is a harmless environmental antigen such as rye grass, pollen, peanuts etc.
    • Re-exposure to allergen leads to mast cell degranulation, histamine release, cytokine production.
  • Th17 cells are also involved in immunopathological disease.
    • Autoimmune and chronic inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and psoriasis.

Immune Evasion Mechanisms of Microbes

  • The primary mechanism used by Mycobacterium tuberculosis is to prevent phagolysosome fusion.
    • They survive in the phagosome and escape into the cytosol, decreasing Ag presentation, and are also resistant to acidification.
  • Many viruses prevent antigen presentation on MHC class I, achieving the same end result through various mechanisms.