T Cell Effector Function 2024 PDF

The adaptive immune response T cell effector functions Dr Natalie Riddell [email protected] 12AY02 @N_Riddell_Immun Wednesday, 20 March 2024 1 Recap- the 3 signals required for T cell activation Signal 1: Antigen recognition CD80/ CD86 Signal 2: Co-stimulation Signal 3: Cytokines inducing diffe...

The adaptive immune response T cell effector functions Dr Natalie Riddell [email protected] 12AY02 @N_Riddell_Immun Wednesday, 20 March 2024 1 Recap- the 3 signals required for T cell activation Signal 1: Antigen recognition CD80/ CD86 Signal 2: Co-stimulation Signal 3: Cytokines inducing differentiation Remember that CD8 T cells also need CD4 help (IL-2 production and increased CD80/86 expression be APC) Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 2 Overview: effector phase and ag elimination T cell maturation Thymus Wednesday, 20 March 2024 Peripheral lymphoid organs Peripheral infected organs Lymphoid and infected organs Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 3 Learning outcomes; T cell effector functions Be able to describe the distinct functions and immune protection provided by Th subsets (Th1, Th2, Th17, Treg and Tfh) Describe how directed T cell migration is achieved Illustrate the effector functions of cytotoxic T (Tc) cells, including killing mechanisms Understand the importance of homeostasis and T cell memory Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 4 CD4 Th cell effector function is largely governed by the cytokines they produce Polarizing cytokine(s) (produced by APC/DC) IFNγ → mΦ (macrophage)/ NK & CD8 T cells IL-4/IL-5 → humoral response IL-12, IFNγ, IL-18 IL-4 IL-10 and TGFβ → antiinflammatory TGFβ, IL-2 IL-1, IL-6, TGFβ Response PRO-INFLAMMATORY INTRACELLULAR PATHOGENS MAST CELL, EOSINOPHIL AND B CELL ACTIVATION & IgE PRODUCTION HELMINTHS / TOXINS/ ALLERGY ANTI-INFLAMMATORY PERIPHERAL TOLERANCE IL-17 → PRO-INFLAMMATORY inflammation/ BACTERIAL/ FUNGAL INFECTION mucosal immunity IL-6, IL-21 TfH cell Wednesday, 20 March 2024 Effector cytokines (produced by CD4) IL-21 → ab production B CELL ACTIVATION, Ig ISOTYPE SWITCH AND AFFINITY MATURATION ALL INFECTIONS Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 5 Updated CD4 Th subsets: Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 6 Effector mechanisms of Th1 cells Periphery Periphery LN ? ? ? ? ? Th1 mediated immunity clears intracellular microbes Macrophage activation Increase IgG3 and IgG2a production by B cells= opsonisation and phagocytosis Neutrophil activation Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 7 Effector mechanisms of Th2 cells ? LN ? ? ? ? Periphery Periphery Th2 cells eliminate helminthic parasites Promote abs which neutralize microbes and toxins IgE production Eosinophil activation Suppress MΦ Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 8 Effector mechanisms of Th17 cells Th17 cell are producers of IL-17 IL-17 inducing chemokines (immune cell attractants) which recruiting neutrophils and monocytes. 2° lymphoid This increases inflammation and protects against bacteria Periphery ? ? Th17 also maintain epithelial barrier function. Th17 are important for mucosal (e.g. gut) immunity Eliminate extracellular bacteria and fungi Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 9 Effector mechanisms of Tfh cells 2° lymphoid ? CD40L ? CD40 ? IL-21 First BCR bound ag is internalised degraded and presented in MHCII to Tfh Wednesday, 20 March 2024 Tfh cell can activate B cells to proliferate and differentiate into ab-producing plasma cells They develop in concert with Th1, Th2 or Th17 cells They help B cells to generate different Ig isotypes (class switch) and undergo affinity maturation in the germinal centre Which Ig isotype and thus FC receptor depends on the most appropriate innate immune effector interaction Thus, unlike Th1, Th2 and Th17, Tfh cells contribute to the eradication of most classes of pathogens Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 10 Effector mechanisms of Tregs 2° lymphoid and periphery 1) Tregs produce anti-inflammatory cytokines ? ? 2) Tregs can provide the CTLA-4 which engages CD80/86 inducing anergy Tregs can inhibit effector responses in 3 ways IL-10 and TGF-b can effect all tissues Blockade and endocytoses of CD80 blocks signal 2= anergy 3) Tregs can “rip-off” and endocytose CD80/86 CD4+ Th cells CD4+ Tregs cells inside Treg CD86 ? Anergy Wednesday, 20 March 2024 Qureshi, O. S., Science Reports 2011 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 11 Summary of CD4 Th effector function Different subtypes of Th cell have different functions, largely depending on the cytokines they make Th1 Th2 Treg Th17 TfH IFNγ IL-4, IL-5 IL-10, TGFβ IL-17 IL-21 Key Th cells are: Th1, Th2, Th17, Tfh and Treg Some Th cells carry out their function in the periphery, activating other immune cells like mφ, PMN, Eosinophils Some Th cells have their effector functions in the lymph node (B cell activation) Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 12 The adaptive immune response T cell effector functions: Part 2 Dr Natalie Riddell [email protected] 12AY02 @N_Riddell_Immun Wednesday, 20 March 2024 14 T cell migration In the lymph nodes In the periphery: Wednesday, 20 March 2024 T cell function and migration; 2 sides of the same coin “Since T cells respond to pathogens only on direct contact with pathogen-derived antigen, they must migrate to sites where antigen is found.” Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 16 T cell function and migration- 2 sides of the same coin T cell 75 litres 1.75x10-13 litres “Imagine now that a few thousand of these balloons must detect within hours tiny structures that arise suddenly anywhere within our planet and are recognizable only by direct contact. Clearly, an intricate guidance system must be at work to accomplish this feat.” Equivalent of an air balloon circumnavigating earth Wednesday, 20 March 2024 Von Andrian and Mackay, NEJM 2000 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 17 T cell migration T cells in circulation are directed to the right part of the body by the interaction between molecules on the T cells and on endothelial cells lining blood vessels Cytokines (produced in the innate immune response) upregulate adhesion molecule expression on endothelium to initiate migration Chemokines are a type of cytokine that attract cells to particular sites (e.g. the lymph nodes or infected tissue) Note: CD8 (Cytotoxic) T cells and some Th cells carry out their function in the periphery (killing or activating other immune cells like mφ, PMN, Eosinophils) But some Th cells have their effector functions in the lymph node (e.g. B cell activation). These are again directed by chemokine gradients. Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 18 T cell migration- recap T cells bind loosely, roll and then enter tissue by diapedesis/ extravasation Extravasation/ migration Lose adhesion Activation of integrins on T cell Stable arrest Naïve entry to lymph node (HEV) Effector entry into inflamed tissue E- and Pselectin CXCL10 LFA-1 and VLA-4 CXCL10 (Note: a similar mechanism underlies migration of granulocytes and monocytes into tissue) Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 19 Chemokine gradient The production of chemokines at infection site = chemokine gradient that attracts the cell into the tissue Infected tissue Lymphocyte https://www.youtube.com /watch?v=ZDMlaWpFiyA (Note: a similar mechanism underlies migration of granulocytes and monocytes into tissue) Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 20 T cell migration HEV in lymph nodes Inflamed peripheral tissue Naïve and effector T cells need to migrate to different tissues Thus upon activation and differentiation, T cells alter their adhesion molecule expression Adhesion molecule expression is partly determined by the APC cell The APC therefore helps direct the T cell to the right tissue e.g. gut Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 21 T cell migration summary https://www.youtube.com/ watch?v=rOb_rburbv0 T cell migration happens in 4 steps (rolling, activation by chemokines, adhesion and extravasation) This is mediated by selectins (rolling) and integrin (firm adhesion) and chemokines and integrin activation T cell adhesion molecule expression changes dependent on cell differentiation (naïve vs effector) and the location of the infection Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 22 Effector mechanisms of CD8+ T cells (CTLs; cytotoxic T lymphocytes) https://www.youtube.co m/watch?v=jgJKaP0Sj5U CD8+ cells: usually cytotoxic in nature Killing is antigen-specific: Target cell must bear the same antigen that activated the naïve CTL presented in MHC- I on its surface. CTL must contact the target cell. Adjacent cells lacking the target antigen in MHC-I are not affected. CTL remain intact after they kill target cells. Each CTL is capable of killing many target cell in sequence. Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 23 Effector mechanisms of CD8+ T cells (CTLs; cytotoxic T lymphocytes) “Selective (ag-specific) serial killers” Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 24 2 mechanisms of CD8+ T cell killing 1. 2. Granzyme/perforin granules Fas – Fas Ligand Both result in apoptosis (programmed cell death) by inducing caspase activation Premature (uncontrolled) cell death Programmed (controlled) cell death Uncontrolled release of cell material induces inflammation Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 25 Granzyme and perforin mediated death https://youtu.be/WdCiaIS2LV4 Focusing of granules at target cell By The National Institutes of Health - https://www.flickr.com/photos/ nihgov/20673870162/in/album72157656657569008 / ,Public Domain, https:// commons.Wikimedia.org/w/index.php?curid=49182097 Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 26 Summary of T cell effector function Once activated in the lymph node many T effector cells leave and carry out their effector functions in tissues Effector cells are attracted to the site of infection by chemokines and adhesion molecules CD8 (Tc) cells kill target cells that present the same Ag/MHCI on their surface by Fas-FasL or granzyme/perforin Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 27 Unconventional T cells Thought to be somewhere between innate and adaptive immunity γδ T cells iNKT cells MAIT Mucosal-associated T cells invariant T cells TCR γ:δ iα:β Semi-iα:β α:β Antigen Non-peptide, lipids Microbial lipids/ glycolipids Microbial-derived vitamin B2 metabolites peptide MHC Independent (likePRR)/ MHC like proteins CD1 MR1 (MHC class I related) MHCI/II Location Skin, mucosal lymphoid tissue, blood Mucosal surfaces Mucosal surfaces Lymph, peripheral tissue, blood Main target Bacterial infections, pathogenic toxins, stress markers Infected/ transformed cells/ bacterial infections bacteria, mycobacteria and yeasts Infected/ transformed cells Function Cytotoxicity (perforin/granzyme) and cytokines (IFNγ, TNFα and IL-17). Can phagocytose Cytotoxcity (mainly Fas:FasL) and cytokine (e.g. IL-2/TNFα Cytotoxcity and cytokine (e.g. IL-17, IL-18, IL-12, IFNI and IFNy) Cytotoxcity (perforin /granzyme and Fas:FasL) and determining immune response (cytokines) Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 28 Unconventional T cells and ILC Thought to be somewhere between innate and adaptive immunity tissue resident mucosal surfaces first responders Ng, 2019 Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 29 Further reading Kuby 8th Edition – – – – Chapters 8: T cell Dev: Positive and negative selection Chapter 10: T cell activation; Helper Subset Differentiation and Memory Chapter 12: Effector responses; Cell mediated Effector Responses Chapter 14: The Adaptive Immune Response in Space and Time; First Contact and Effector and Memory Cell Response Male, Brostoff, Roth, Roitt 8th Edition – Section 2: Chapters 9&10 Many of these illustrations are from “Basic Immunology” Abbas, Lichtman and Pillai. Elsevier. ISBN 978-0-323-39082-8 or “Janeway’s Immunobiology” Murphy, Travers and Walport. Garland Science. ISBN-13: 978-0815341239 Also see “Useful links for immunology” document including British Society for Immunology (BSI) Bitesize; https://www.immunology.org/public-information/bitesized-immunology Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 30 T Cell Activation, Differentiation and effector functions by Dr Natalie Riddell [email protected] 12AY02 @N_Riddell_Immun Wednesday, 20 March 2024 31