Lecture 12: Effector T cells and their Functions

Mechanism of CTL Killing: Fas-FasL

Fas-FasL interaction between the CTL and the target cell -all of our nucleated cells express Fas receptors (CD95) -effector CTLs express FasL (CD178). If a CTL recognizes its antigen displayed in Class I MHC and binds to the target cell, there is now sufficient time for FasL on the CTL to bind to the Fas receptor on target cells. -The Fas-FasL(CD95-CD178) interaction activates a caspase pathway, stimulating apoptosis

TH1-mediated stimulation of B cells

IFN-y secreted by effector TH1 cells also functions in the stimulation of B cells -IFN-y results in the B cells producing IgG antibodies via class switching -IgG antibodies are good opsonins and can activate complement

Limiting T cell Responses in the Tissues

In order to limit inflammatory responses in the tissues, the effector functions of T cells need to be regulated/controlled -PD-1 is an inhibitory receptor and is expressed by effector T cells in the tissues -in response to inflammatory stimuli, PD-1 ligands are upregulated on APCs -Binding of a PD-1 ligand to PD-1 results in T cell inhibition Known PD-1 ligands are PD-L1 and PD-L2

Overview: Types of Effector Th cells

upon activation, mature, naive CD4+ T cells (often called Th0 cells) differentiate into one of three subsets, TH1, TH2, TH17 which subset develops depends on stimuli present during the early immune response -type of antigen --for TH1: intracellular microbes --for TH2: helminths (and allergens) --for TH17: Extracellular bacteria/fungi cytokines produced in response to the initiating antigen: -IL-12 + IFN-y -> Th1 -IL-4 -> TH2 -TGF-B + IL-6 -> Th17

Clinical Application: Role of CTLs in Disease

Destruction of infected cells by CTLs is a cause of significant tissue injury in some diseases, such as hepatitis. The immune-mediated destruction of hepatocytes is what is causing the majority of the clinical manifestations, such as jaundice, associated with these viral infections.

Cell mediated immunity

Cell mediated immunity (CMI) of the adaptive immune system is the effector function of T lymphocytes and serves as the defense mechanism against microbes that survive and replicate within phagocytes and nonphagocytic cells -cytotoxic T cells directly kill infected cells -helper T cell cytokines activate macrophages to kill phagocytksed microbes, augment APC function, stimulate NK cell function, and can also regulate humoral immune responses as well. Defects in T cell result in an increased susceptibility to infections

Mechanism of CTL Killing: Degranulation

Degranulation = release of granular contents: -perforin: pore forming protein -granzymes: serine esterases perforin monomers insert and polymerize forming a channel for the granzymes to enter and activate an apoptotic (caspase) pathway

Overview: Effector Helper T cells

Each helper T cell subset secretes a different cytokine profile to direct the immune response to the initiating antigen

TH-1 mediated activation of CTLs

Effector TH1 cells also participate in the activation and differentiation of naive Tc cells into effector CTLs -Panel A: effector TH1 cell secretes IL-2 and IFN-y that can augment Tc cell activation -Panel B: Effector TH1 cells can augment APC activity via CD40-CD40L binding to become more effective at activating Tc cells

TH-1 Mediated Augmentation of Inflammation

Effector TH1 cells also secrete TNF, which acts on the vascular endothelium to increase expression of CAMs and production of chemokines -This will promote the extravasation and chemotaxis of WBCs from the vasculature into and through tissue spaces -If the pathogen is resistant to the phagocyte's intracellular killing mechanisms, granuloma formation can occur.

TH1-mediated activation of macrophages

Effector TH1 cells secrete IFN-y and also express CD40L = the ligand for CD40 that is expressed by APCs -both IFN-y and the CD40-CD154 binding interaction augment the APC and phagocytic functions of macrophages -this is known as "classical macrophage (M1) activation."

"Alternative Macrophage Activation" by TH2 cells

Effector TH2 cells secrete Il-4 and IL-13 that stimulate macrophages differently than IFN-y from TH1 cell does -TH2 cells stimulate macrophages to synthesize factors that promote collagen synthesis and fibrosis in chronic parasitic diseases and allergies -These "alternatively activated" (M2) macrophages also secrete IL-10 and TGF-B = anti-inflammatory cytokines that suppress "classically activated" macrophages and a TH1 cell response

Introduction: Effector Functions of T Cells

Effector helper T cells (Th cells) link the recognition of microbes with recruitment of microbes with recruitment and activation, through cytokine secretion, of other WBCs that destroy the microbes Effector cytotoxic T cells (CTLs) recognize and kill host cells infected with microbes that replicate in the cytoplasm

Migration of Effector T cells

Recall, T cell activation and differentiation occurs within the secondary lymphatic tissues differentiated effector T cells exit the secondary lymphatics into circulation and home to regions of infection or injury (within the peripheral tissues) -it is within the periphery where the effector functions of T cells occur

Clinical Application: Role of TH17 Cells in Disease

TH17 cells are important in the pathogenesis of several inflammatory diseases, such as inflammatory bowel disease (IBD) -when TH17 cells predominate instead of regulatory T cells, strong inflammatory responses that can damage the intestinal epithelium can occur

TH1 Cells

The TH1 subset differentiates during activation of naive T cell in response to many intracellular microbes that stimulate macrophages, NK cells, and conventional dendritic cells -innate immune cells secrete IL-12 and IFN-y TH1 cells are the major effector T cell population regulating a cell-mediated immune response against intracellular pathogens (and tumor cells)

TH17 Cells

The TH17 subset differentiates during activation of a naive T cell in response to extracellular bacteria and fungi that stimulate inflammatory responses within the tissues -Tissues secrete TGF-B; IL-6 from inflammation TH17 cells are the major effector T cell population regulating immune responses against extracellular pathogens and stimulate strong inflammatory responses

Cytotoxic T cells (CTLs)

The primary function of CD8+CTLs is to killl: kill cells infected with an intracellular microbe and to kill tumors CD8+T cells differentiate into effector CTLs during antigen-induced activation -activation of CD8+ T cells can involve TH1 cells -Effector CTLs recognize infected or tumor cells via TCR-MHC Class I interaction; recognition of antigen by the effector CTL triggers its killing capabilities --Two mechanisms are used by the CTL to kill target cells; both mechanisms induce apoptosis in the target cell

Functions of Effector TH17 Cells

The primary function of effector TH17 cells is to destroy extracellular bacteria/fungi by inducing neutrophilic inflammation -The signature cytokines secreted by effector TH17 cells in response to extracellular bacteria and fungi are IL-17 and IL-22 -IL-17 stimulates the production of chemokine and proinflammatory cytokines to recruit PMNs and also stimulates the producton of anti-microbial peptides -IL-22 promotes epithelial integrity and also stimulates production of antimicrobial peptides and mucins

Functions of Effector TH2 Cells

The primary function of effector TH2 cells is to stimulate IgE and eosinophil-mediated reactions that eradicate helminthic infections. the signature cytokines secreted by effector TH2 cells in response to helminths (and various allergens too) are IL-4, IL-5 and IL-13 IL-4 stimulates B cells to class switch to IgE IL-5 activates eosinophils to degranulate IL-4 and IL-13 stimulates peristalsis and increased secretion in the gut as well as alternative activation of macrophages

Types of Effector helper T cells (Th cells)

There are five main subtypes of helper T cells: -TH1, TH2 and TH17 secrete cytokines that regulate immune actions against distinct pathogens -TFH cells secrete cytokines that regulate germinal center reactions -Treg cells secrete cytokines that help to limit immune responses

Clinical Application: Keeping T cells active

monoclonal antibodies against PD-1 and PD-L1 are being used therapeutically to block the inhibition of effector T cells, keeping them active longer! Atezolizumab (Tecentriq®): anti-PD-L1 monoclonal antibody FYI: Approved for use in metastatic urothelial carcinoma (mUC) & non-small cell lung cancer (NSCLC). Nivolumab (Opdivo®): anti-PD-1 monoclonal antibody FYI: Approved for use in metastatic melanoma & NSCLC; also being used in combination with Ipilimumab (Yervoy®) with great promise!

Clinical Application: Role of TH1 cells in disease

some antigens can enter the tissues, bind to proteins in the skin, and lead to strong activation of TH1 cells this activation of effector TH1 cells, if exaggerated or inappropriate, leads to the development of a Type IV hypersensitivity response

Clinical Application: Role of TH2 cells in disease

some antigens trigger an inappropriate IgE response instead of a more "protective" IgG response -These antigens mimic helminth antigens in allergic individuals -this inappropriate activation of effector TH2 cells results in the development of a Type 1 hypersensitivity response

TH2 cells

the TH2 subset differentiates during activation of a naive T cell in response to helminths (and allergens) that stimulate IgE production and mast cell and eosinophil degranulation -mast cells and eosinophils secrete IL-4 TH2 cells are the major effector T cell population in regulating immune responses against helminths (and allergens)

Functions of Effector TH1 Cells

the primary function of effector TH1 cells is to activate macrophages to ingest and destroy microbes. In addition TH1 cells also can participate in activation of CTLs. the signature cytokine secreted by effector TH1 cells in response to intracellular infections or tumor cells if IFN-y -but TH1 cells also produce IL-2 and TNF TH1 cells can activate macrophages and Tc cells TH1 cells stimulate B cell production of opsonizing antibodies TH1 cells participate in inflammation