Cell-Mediated Immunity - Effector Functions (2025)

BIOM 611G, Medical Microbiology PCOM Georgia CELL-MEDIATED IMMUNITY-2: EFFECTOR FUNCTION OF T-CELLS Valerie E. Cadet, PhD Assistant Dean of Health Equity Integration Pro...

BIOM 611G, Medical Microbiology PCOM Georgia CELL-MEDIATED IMMUNITY-2: EFFECTOR FUNCTION OF T-CELLS Valerie E. Cadet, PhD Assistant Dean of Health Equity Integration Professor of Microbiology and Immunology BMS1 & BMS2 Department of Biomedical Sciences January 23, 2025 LEARNING OBJECTIVES Through the study of this content and recommended reading, the successful student will be able to……. 1. Identify, compare and contrast the effector cytokines and cellular mechanisms involved in Th1, Th2 and Th17 responses. 2. Diagram CD4+ Th1 cell-mediated macrophage activation for cytotoxic activity, particularly the role of CD40L and IFN-g. 3. Describe how the relative dominance of CD4+ Th1 or CD4+ Th2 cells influences the clinical course of infection by Mycobacterium spp. 4. Outline the mechanisms for CTL-mediated target cell recognition and killing. Contrast this with the natural killer cell-mediated target cell recognition and killing. 2 WHERE WE’VE BEEN AND WHERE WE’RE GOING IN CELL-MEDIATED IMMUNITY (CMI) 3  STEPS IN CD4+ T CMI RESPONSES 4  Identify, compare and contrast HOW DO THE effector cytokines and cellular mechanisms DIFFERENT T involved in Th1, Th2 and Th17 responses CELL SUBSETS Describe how relative dominance of DO WHAT THEY CD4+ Th1 or CD4+ Th2 cells influences the clinical course DO? of infection by Mycobacterium spp. 5  CD4+ TH1 CELLS ▪ Differentiation ▪ IFN- γ and IL-12 🡪 T-BET, STAT1, and STAT4 transcription factors ▪ Inhibited by IL-4 ▪ Function ▪ Secrete IFNg for classical (M1) macrophage activation to increase phagocytosis and killing of microbes in phagolysosomes ▪ Other cytokines secreted ▪ TNFα: Activation of neutrophils & endothelial cells promoting inflammation ▪ Chemokines CCL3, CCL4, CCL5: recruit macrophages to sites of chronic inflammation 🡪 granuloma formation (DTH response) ▪ Enhances Ag presentation by pAPCs ▪ B cell isotype switching to IgG (by Tfh cells) 6  MACROPHAGES (& B CELLS) NEED TH1 ▪ CELLS…WHY? Differentiated CD4+ T cells express CD40L and secrete cytokines ▪ CD40L binds CD40 on macrophages or B cells ▪ Essential for Th1 and Th2 effector function ▪ Cytokines bind receptors on the same cells ▪ Combo of signals delivered by CD40/CD40L and cytokine receptors ▪ activate macrophages (CMI) 🡪 killing of phagocytosed microbes ▪ activate B cells (humoral immunity) 🡪 proliferation, antibody secretion and class switching ▪ Clinical Correlation ▪ Mutations in CD40 or CD40L 🡪 Hyper IgM Syndrome ▪ No class switching to IgG (hence hyper IgM) ▪ CMI also impaired because no activation of macrophages 7 Diagram CD4+ Th1 cell-mediated macrophage activation for cytotoxic activity, particularly the role of CD40L and IFN-γ CD4+ TH2 CELLS ▪ Differentiation ▪ IL-4🡪 GATA-3 and STAT4 transcription factors ▪ Inhibited by IFNγ ▪ Function ▪ Secrete IL-4 to stimulate production of IgE and mast cell growth factor. IgE 🡪 activation of mast cells by protein antigens and opsonizes helminths. ▪ Stimulates production of other antibody isotypes that may neutralize microbes and toxins (IgG) but do not opsonize microbes for phagocytosis or activate complement by classical pathway ▪ IL-5: activates eosinophils and mast cells. Acts as chemotactic agent for them ▪ IL-13: (along with IL-4) alternative macrophage activation (M2) 🡪 tissue repair (+) and fibrosis (-) 8  CD4+ TH2 CELLS CARRY OUT MULTIPLE FUNCTIONS 9 MACROPHAGE ACTIVATION: M1 VS. M2 10 BALANCE BETWEEN TH1 & TH2 CELLS MAY INFLUENCE OUTCOME OF INFECTIONS ▪ Overexpression of Th1 can lead to immune-mediated inflammatory tissue damage ▪ Overexpression of Th2 cells can lead to increased risk of atopic (allergic) responses. Mycobacterium leprae 🡪 leprosy ▪ Lives inside macrophages and may be eliminated by CMI ▪ Tuberculoid leprosy (Th1) ▪ If strong CMI 🡪 M. leprae–specific CD4+ Th1 and macrophages clear bacteria ▪ Less injurious inflammatory granuloma reactions occur (skin lesions) ▪ Lepromatous leprosy (Th2) ▪ High bacteria count (defective clearance) ▪ If defect in Th1 activation or dominant Th2 🡪 M. leprae–specific CD4+ Th2 unable to eradicate 🡪 more destructive lepromatous leprosy 11 ▪ May be true for other infectious diseases  CD4+ TH17 CELLS ▪ Differentiation ▪ IL-1, IL-6, IL-23, TGF-beta🡪 RORγT transcription factor ▪ Inhibited by IFNγ & IL-4 ▪ Function ▪ Secrete IL-17 to induce neutrophil-rich acute inflammation ▪ Stimulates production of AMPs inc. defensins, from numerous cell types ▪ IL-22 ▪ Maintains epithelial integrity, by promoting barrier function of epithelia, stimulating repair reactions, and inducing production of anti-microbial peptides, particularly in skin and GI tract  CD4+ TH17 CELLS ▪ Primary Role: Secrete cytokines which mediate neutrophil recruitment and induce inflammation, thus destroying extracellular bacteria and fungi VARIOUS FATES FOR NAÏVE 🡪 EFFECTOR CD4+ T CELLS 14  Outline CD8+ CTLS mechanisms for RECOGNIZE A CTL-mediated target cell recognition and UNIQUE killing SIGNAL TO Contrast KILL TARGET with the NK cell-mediated target CELLS cell recognition and killing 15  STEPS IN CD8+ T CMI RESPONSES 16  ACTIVATION & FUNCTION OF CD8+ T CELLS Differentiation Stimulated by recognition of MHC I–associated antigens presented by DCs typically or via cross-presentation in LN Inhibited by PD-1 May block activation of CTLs 🡪 PD-1–mediated T cell exhaustion 🡪 chronic viral infections and tumor evasion Function Kill infected or tumor cells Secrete IFNγ Activates phagocytes to ingest and kill microbes 17  CD8+ CTL PRIMARY KILLING MECHANISM 1. Naïve CD8+ cells initially activated in secondary lymphoid tissue 2. Activated CD8+ must now ‘find’ cells in need of CTL ‘help’ thus, circulating throughout tissues of body as CTLs, scrutinizing each MHC I being displayed by nucleated cells 3. On recognition of appropriate MHC class I complex, series of events are initiated by CTL 🡪 lysis of target cell 4. Although contact between CTL and target cell lasts only few minutes, CTL delivers "kiss of death" to target cell in form of perforin granules and granzymes 5. Perforin granules polymerize to form pores in cell, creating electrolyte imbalance (osmotic lysis) 6. Granzymes enter through pores and activate apoptotic pathways 18 ALTERNATE MECHANISMS OF CTL KILLING 1. Secretion of TNF-β (lymphotoxin) ▪ Upregulation of TNFR on target cell ▪ Induces target cell apoptotic pathway 2. IFNγ secretion by CTLs ▪ Upregulation of MHC I and Fas (death-inducing receptor CD95) on target cells ▪ Activated CTLs express Fas ligand ▪ Fas-FasL interaction ▪ Binding of Fas on target cell to FasL on CTL leads to apoptosis of target cell 19 Typical CTL killing is shown  CTL RELEASING EFFECTOR MOLECULES Green: CTL Red: Target cell Red dots: cytotoxic granules 20 Fig 9.49 Janeways’s Immnuobiology, 10ed. CD4+ AND CD8+ CELLS WORK TOGETHER TO INCREASE KILLING IN INTRACELLULAR INFECTIONS 21  SUMMARY: OUTCOME OF CMI REACTION S CD4 + effector T cells function 🡪 cytokines 22 Fig. 10.1 CD8 + effector cells kill infected cells and tumor cells SUMMARY: PROPERTIES AND ROLE OF IMPORTANT CYTOKINES PRODUCED BY T CELLS (AND OTHER CELLS) 23 THOUGHT QUESTIONS What signals are needed to activate T lymphocytes, and what cellular receptors are used to sense and respond to these signals? How are the few naive T cells specific for any microbe converted into the large number of effector T cells that have specialized functions and the ability to eliminate diverse microbes? What molecules are produced by T lymphocytes that mediate their communications with other cells, such as macrophages, B lymphocytes, and other leukocytes? 24 REMEMBER THE BIG PICTURE 25