chapter 6 Effector mechanism of T Cell-Mediated Immunity

(1) Many bacteria, fungi, Protozoa can resist the killing mechanisms of these phagocytes.

(2) viruses that infect phagocytic and nonphagocytic cells.

CD4+ T Cells

(CD8+ T Cells can eradicate infections without a requirement for phagocytes)

Th1

Th2

Th17

Tfh(follicular helper cells)

Cytokines

(All these types of Immune responses depend on CD4+ helper cells, they are able to stimulate distinct immune effector mechanisms)

• stimulate phagocyte-mediated killing of ingested microbes

• signature cytokine: interferon γ (IFN-γ) - most potent macrophage-activating cytokine

• Acting through CD40L and IFN-γ increases ability of macrophages to kill phagocytosed microbes

• Binding of CD40L to CD40 on macrophages functions together with IFN-γ binding to its receptor on same macrophage to trigger biochemical signaling pathways that lead to reactive oxygen species (ROS) and nitric oxide (NO) and activation of lysosomal proteases

Net result of CD40-mediated IFN-γ mediated activation: macrophages become strongly microbicidal and destroy most ingested microbes

Classic macrophage activation

Also secrete cytokines that stimulate inflammation and express increased levels of MHC molecules and costimulators, which amplify T Cell response

Driven by a combination of TCR signaling and cytokines IL-12 and IFN-γ

• In response to many bacteria,viruses - dentritic cells and macrophages produce IL-12 and NK cells produce IFN-γ

• T Cells are exposed to these cytokines if naive T cells recognize the antigens of these microbes

• IL-12 and IFN-γ activate transcription factors Stat4 and Stat1

• Antigen-induced signals in combination with cytokines induce expression of transcription factor T-bet (Th1 development and function)

• These transcription factors stimulate expression of IFN-γ and other proteins involved in migration of Th1 cells to site of infection

• IFN-γ activates not only macrophages, promotes also Th1 development and inhibits development of Th2 and Th17 cells

• induced by parasitic worm infections

• Promote IgE-, mast cell- and eosinophil mediated destruction of these parasites

• Signature cytokines: IL-4, IL-5 and IL-13

• Principal target cells: Eosinophils

• When Th2 and related Tfh cells encounter antigens of Helminths -> T cells secrete their cytokines

• Tfh cells secrete IL-4 -> stimulates production of IgE antibodies

• IgE antibodies coat Helminths and thus help in their clearance

• Eosinophils use their Fc receptors to bind to IgE and are activated by IL-5 (produced by Th2)

• Activated Eosinophils release their granules -> toxic to parasites

• IL-13 stimulates mucus secretion and intestinal peristalsis -> increasing expulsion of parasites in intestines

• IgE binds to mast cells and activates them -> secretion of chemical mediators that stimulate inflammation and proteases that destroy toxins

Classical macrophage activation is inhibited

• IL-4 and Il-13 inhibit classical

Alternative macrophage activation M2

• activate macrophages to secrete growth factors (act on fibroblasts -> increase collagen synthesis + induce fibrosis

Allergens

• allergens triggers mast cell and eosinophil activation

• differentiation of naive CD4+ T Cells to Th2 cells stimulated by IL-4 (produced by mast cells, other tissues)

• IL4 activates transcription factor Stat6

• Combo of IL4 and antigen-induced signals induce expression of GATA-3

• GATA-3 -> required for Th2 differentiation

• these TF stimulate expression of Th2 cytokines and promote Th2 response

• IL-4 enhances further Th2 differentiation

Cytokines: IL-17, IL-22

Target Cells: Neutrophils

Host Defense: Extracellular fungi/bacteria

Functions of Cytokines:

IL-17

• Stimulates chemokine secretion from other cells for leukocyte recruitment

• Stimulates production of defensins (function like endogenous antibiotics)

• Induce inflammation (prevent colonization, don’t kill, just pretend them from invading)

• Stronger and longer inflammation response than in innate immunity

IL-22

• Maintain integrity and repair damage of epithelial barriers

• cytokines from macrophages and dendritic cells response to fungi and bacteria stimulate Th17 differentiantion

• IL-1; IL-6 and IL-23 stimulate Stat3 (TF)

• Signals induced by these inflammatory cytokines and transforming growth factor β (TGF-β) in combination with TCR signals -> expression of RORyT (TF)

• TF are needed for differentiation of Th17

• TGF-β is a powerful inhibitor of immune response but when present with IL-6 or IL-1 it promotes Th17 development

1. CD8+ T cells recognize MHC 1 - antigen on an infected tissue cell and convert to CTLs (effected cells

   • Microbes in vesicles in cytosol, freely escaped in cytosol

   • Microbes captured by dendritic cells and then transferred to cytosol (Cross presentation)

2. Requires:

   • Antigen, Costimulation and help from CD4+ for activation

   • After activation no need for costimulation

3. Immune synapse:

   • TCR, CD8 signaling proteins cluster and becomes surrounded by LFA-1 Integrin -> bind to target cells

4. Release of granules

   • contain performing and granzymes into the synapse

   • Enter infected cells recognized by T lymphocyte and induce apoptosis

5. Fas Ligand on CTL bind to death inducing receptor Fas (CD95) on antigen -> apoptosis

6. Dead cells -> phagocytosed and eliminated, while CTLs can continue killing after detaching from cell

• disrupt integrity of plasma and endosomal membranes -> delivery of granzymes to cytosol

• Facilitates entry

Cleave and activate caspases -> induce apoptosis

• Myobacterium Tuberculosis

• Legionella Pneumophilia

• Listeria Monocytogenes

All inhibit fusion of phagosomes with lysosomes and escape into cytosol and thereby resist microbicial actions of phagosomes

• Production of Class 1 MHC molecules

• Block of transport of antigenic peptides from cytosol to ER

• Removes newly synthesized MHC from ER

  -> reduces surface expression of MHC class 1 molecules

Inhibitory cytokines

Destroy cytokine receptors that would trigger cell mediated responses

• NK cells are activated by cells lacking MHC 1

• This means that host Defense avoids immune evasion by microbes

• CTLs recognizes MHC class 1 antigen peptides -> viruses inhibits MHC class molecules ->NK cells notices MHC1 deficency

Chronic infection by viruses that express inhibitory receptors such as PD-1 and

CTLA - 4 thus inhibiting the effector functions of CTLs