T cell dev and activation 2024.pdf

T Cell development and activation: Part 1 Dr Natalie Riddell [email protected] 12AY02 @N_Riddell_Immun Wednesday, 20 March 2024 1 Learning outcomes; T cell development and activation 1) The role of T cells in immune responses 2) The maturation and selection process for CD4+ and CD8+ T cells 3)...

T Cell development and activation: Part 1 Dr Natalie Riddell [email protected] 12AY02 @N_Riddell_Immun Wednesday, 20 March 2024 1 Learning outcomes; T cell development and activation 1) The role of T cells in immune responses 2) The maturation and selection process for CD4+ and CD8+ T cells 3) Stages and development of T cell mediated immunity (CMI)- with some terminology 4) The 2 steps to T cell activation 5) The 3rd signal and T cell differentiation Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 2 What is adaptive immunity (re-cap) “An immune response that becomes more powerful following repeated encounters with the same antigen” The utilisation of highly specific antigen receptors has several advantages: – Pathogens lacking stereotypical PAMPs can be recognised – Responses can be highly specific for a given pathogen – The specificity of the response allows for immunological memory 1. Highly diverse populations of cells 2. Pathogen-specific cells expand (and improve themselves) in the repertoire. 3. Resolution (contraction) and MEMORY Specific immunity can be achieved by either natural exposure (e.g. chickenpox) or artificially by vaccination (e.g. MMR/COVID) Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 3 Why do we need T cells? T cells aid the clearance of phagocytosed and intracellular microbes in macrophages and infected cells, respectively (Cell mediated immunity: CMI) They also help B cells produce different Ig isotypes and high affinity antibodies Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 4 Learning outcomes; T cell development and activation 2 4 T cell maturation Theme 3 5 3 Wednesday, 20 March 2024 Terminology Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 5 T cell maturation recap- central tolerance T cells maturation and selection occurs in the thymus (only self-ag present) Positive selection ensure adequate recognition of MHC presented ags https://www.youtube.com/w atch?v=9E_UxnC_L2o&t=6s Negative selection averts recognition of self and prevents autoimmunity: central tolerance- (we’ll discuss peripheral tolerance later) Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 6 T cell terminology; Naïve, effector and 3 memory T cells T cells are either naïve, memory or effector cells Naïve cells have not been stimulated by antigen since leaving the thymus Effector T cells have specialised functions e.g. secretion of cytokines or lysis of target cells. Effector cells derive from naïve or memory cells, are short-lived, in an activated state but require further stimulation for full function Memory cells have had antigen presented to them & return to resting state. They are usually long-lived and can be subsequently reactivated Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 7 T cell terminology; Naïve, effector and 3 memory T cells Draining lymph nodes Wednesday, 20 March 2024 Peripheral infected organs Lymphoid and infected organs Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 8 3 Naïve, effector and memory Effector-memory are like effector upon activation Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 9 Magnitude 3 Naïve, effector and memory T cells Effectors Naive Effectors Memory Effectors Memory Time Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 10 Effectiveness of the Pfizer Vaccine https://www.nytimes.com/interactive/2020/health/pfizer-biontech-covid-19-vaccine.html Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 11 4 T cell activation Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 12 4 T cell activation Step 1: Antigen recognition Helper T cells – Th cells CD4+ – Antigen presenting cells only – MHC class II – assist other white blood cells. Cytotoxic T cells – Tc cells CD8+ – All nucleated cells – MHC class I – Kill intracellularly BUT THIS IS NOT ENOUGH TO ACTIVATE T CELLS! Wednesday, 20 March 2024 Prof. Deborah DunnWalters’ and Theme 3 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 13 4 T cell activation; 2 signals are necessary Step 1: Antigen recognition by TCR/MHC interaction Step 2: Co-stimulatory molecules interact With both signals present, the T cell activates and undergoes “clonal expansion” Reassurance to “fire-up” Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 14 4 T cell activation: Co-stimulatory molecules Signal 1. TCR/MHC Signal 2. Co-stimulatory Note: CD80/CD86 (human) = B7-1/B7-2 (murine) Wednesday, 20 March 2024 Co-stimulatory signals are the same for CD4 and CD8 T cells Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 15 4 T cell activation: Co-stimulatory molecules Lck: lymphocyte specific tyrosine kinase ITAM: immunoreceptor tyrosine-based activation motif With both signals present, signal transduction occurs, the T cell activates, and undergoes “clonal expansion” Activation of transcription factors = gene and protein expression Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 16 4 T cell activation; clonal expansion The second signal results in the proliferation of naïve T cells induced by the production of cytokine, mainly IL-2, which induces proliferation. Cytokines act primarily by autocrine mechanism, i.e. by secreting cytokines that act on self, since T cells also expresses the cell surface receptors for these cytokines (eg IL-2R) IL-2R clonal expansion IL-2 TCR recognising one particular epitope Wednesday, 20 March 2024 All T cells in expanded clone recognise the same epitope Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 17 4 T cell activation; why 2 signals? Expression of co-stimulators is regulated and ensures that T cells respond at the correct time and place CD80/CD86 expression is induced by microbial products (e.g. PAMPs) and cytokines (IFN-γ) Mature DCs express the highest levels of co-stimulators and therefore are the most potent stimulators of naïve T cells In what circumstance would antigen be presented without co-stimulation? Reassurance to “fire-up” Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 18 4 T cell activation; APC upregulate 2nd signal ligand in response to microbes Ag uptake mode dendritic Cell (DC) TNF, IFNy & PAMPs = DC maturation Ag presentation mode DC Wednesday, 20 March 2024 Note: CD80/CD86 (human) = B7-1/B7-2 (murine) Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 19 T cell activation or anergy MHC/TCR only = anergy MHC/TCR + co-stimulation = activation Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 20 Peripheral tolerance If expressed on the T cell, CTLA-4 (inhibitory receptor) can engage CD80/86 instead of CD28. This can also induce anergy Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 21 Peripheral tolerance and anergy Tregs (a type of CD4 T cell) can also provide the CTLA-4 which engagesCD80/86 and stop activation Lack of co-stimulatory molecule expression by APC AND CTLA-4 expression by T cell/Treg can prevent cell activation and promote tolerance to self-antigens Anergy Balance between activation and tolerance is crucial CD80/CD86 (human) = B7.1/B7.2 (murine) Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 22 4 Check point inhibitors (inhibitors of inhibitors activate T cells in cancer) Winners of The Nobel Prize in Physiology or Medicine 2018!!! Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 23 T Cell development and activation: Part 2 Dr Natalie Riddell [email protected] 12AY02 @N_Riddell_Immun Wednesday, 20 March 2024 25 4 T cell differentiation Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 26 4 T cell differentiation T cells are multifunctional; the Swiss army knife of the immune system Activate neutrophils Activate macrophages Kill infected cells There are many different type! CD4 (Th1, Th2, Th17, Tregs, Tfh) CD8 γδ T cells Invariant natural Killer T (iNKT)cells Produce cytokines Regulate/ inhibit immune responses (tolerance) Wednesday, 20 March 2024 B cell help/ ab class switching/ affinity maturation Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 27 4 The 3rd Signal dictates T cell differentiation In addition to the 2 signals which activate a naïve T cell and cause it to proliferate, there is a THIRD signal which directs T cell differentiation into different subsets The 3rd signal is CYTOKINES The CYTOKINES are made by the same APC that provided Ag/MHCII and costimulation & by other cells to create a “cytokine environment” Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 28 Differentiation of Th cells Different cytokines in the cytokine environment produces a different type of effector CD4 (Th) cell Each subset is induced by the types of microbes that subset is best able to combat Also known as “T cell polarisation” Each subset has different functions…. Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 29 IFNγ TNFα IL-2 Th cell subsets: IL-12, IFNγ, IL-18 IL-4 IL-5 IL-13 IL-4 TGFβ, IL-2 TGFβ IL-10 IL-1, IL-6, TGFβ IL-17 IL-22 IL-6, IL-21 TfH cell IL-4 IL-21 Th cell functions: ANTI-INFLAMMATORY Periferal Tolerance PRO-INFLAMMATORY BACTERIAL INFECTION Wednesday, 20 March 2024 PRO-INFLAMMATORY INTRACELLULAR PATHOGENS B CELL ACTIVATION IN FOLLICLES B CELL ACTIVATION & Ab PRODUCTION HELMINTHS / TOXINS 30 Th1 (CMI) or Th2 (humoral) differentiation Subset Th1 Th2 Th17 Treg Tfh Wednesday, 20 March 2024 Polarizing factor IL-12 (IL-18/IFNγ) IL-4 TGFβ, IL-1, IL-6 TGFβ, IL-2 IL-6, IL-21 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 31 Th1 and Th2 cross-regulation Cytokines actively induce TH1 or TH2 differentiation. At the same time, T-Bet represses expression of the TH2-defining master transcriptional regulator, GATA-3, as well as expression of the effector cytokines IL-4 and IL-5. Reciprocally, IL-4 promotes expression of GATA-3, which up-regulates the synthesis of IL4 and IL-5, and at the same time represses expression of T-Bet and the TH1 effector cytokine IFN-γ. Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 32 Activation of CD8+ T cells- cytotoxic T lymphocytes (CTLs) CD8+ T cells recognise antigen presented by MHC Class I (e.g. virally infected cells) Their activation requirements are the same as Th cells (2 signals) BUT they require more co-stimulation than Th cells This is USUALLY provided by effector CD4+ Th (Th1 or Th17) cells that have recognised related antigen on the APC Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 33 Activation of CD8+ T cells- cytotoxic T lymphocytes (CTLs); Th help CD4+ Th cells help activate Tc cells by providing cytokines and CD40L When the CD4+ Th cell is activated by the APC (usually a DC), this make it secrete IL-2 and express CD40L IL-2 acts directly on the CD8 T cell CD40L binds to CD40 on the APC, which stimulates it to make more costimulatory CD80/CD86, enhancing activation of the CD8 T cell CD80/CD86 (human) = B7.1/B7.2 (murine) Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 34 Activation of CD8+ T cells- cytotoxic T lymphocytes (CTLs) Because of this requirement T cells must be activated by related antigens presented by BOTH MHCI and MHCII on the same APC Problems….. Most viruses are not trophic for DCs (and therefore would not be endogenous ag in these cells) So how does this work??? Wednesday, 20 March 2024 DC blue CD4+ T cell red CD8+ T cell green Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 35 Cross Presentation and CD8 T cell activation What you learned about antigen presentation by MHC class I and II in theme 3 is an oversimplification ~25% of MHC class I molecules are presenting peptides from exogenous antigens “Cross presentation” is the presentation of exogenous antigens on MHC class I Could be viral particles, apoptotic infected cells etc Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 36 Activation of CD8+ T cells- cytotoxic T lymphocytes (CTLs) Peripheral infected organ/ tissue Wednesday, 20 March 2024 Peripheral lymphoid organs Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 37 Summary of T cell activation T cell activation requires 2 signals (MHC/ag-TCR and costimulation For Th cells CD80/86-CD28 is enough A 3rd signal (cytokine environment) defines the type of T effector you get For Tc cells you need Th help; activated and bound by the same APC (CD40-CD40L) Cross presentation of exogenous antigens to MHC-I is important for CD8+ T cell (CTL) activation Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 38 Dynamics of T cell response Antigen recognition Activation Antigen elimination (next session) Contraction/ Homeostasis Memory Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 39 Contraction/ homeostasis As antigen is cleared, the stimulus for co-stimulation subsides and T cell responses decline New effector cells are not activated Effector cells age and die by apoptosis and are cleared by phagocytes Almost 95% of effector T cells die once the antigen is eliminated A small proportion remain as long-lived memory cells Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 40 CD4 Th subset overview (notes from early work) Th1: Inflammatory T cells, produce TNFα/IFNγ -- Mediate inflammatory immune responses (through activation of macrophages and cytotoxic T cells). Th2: produce IL-4, IL-5, IL-13 – Involved in the clearance of parasitic infections and enhanced eosinophil/mast cell responses. Th17: produce IL-17, IL-22 -- Thought to play a role in inflammation and tissue injury, important for mucosal/epithelial immune response. Treg: Regulatory T cells – produce IL-10, TGFβ -- Play a suppressive or regulatory role. Can be natural or inducible TFH : Follicular helper T cells – found in 2° lymphoid follicles. This T cell subset are those that activate B cells. Produce IL-4 and IL-21 Wednesday, 20 March 2024 Dr Natalie Riddell, [email protected], 12AY02, @N_Riddell_Immun 41