“Introduction to immunology – what clinicians need to know”
Paul U Cameron Clinical Immunologist,
ID department Alfred Hospital and Monash University, Doherty Institute for Infection and Immunity,
University of Melbourne
Immunotherapy in HIV
⚫ Objectives for induction of remission or a cure of HIV are;
− Inducing expression of HIV from latency LRA
− Increasing immune mediated clearance Effective antiviral immunity
− Increasing cell death mediated by innate or adaptiveimmunity
Deeks nature 2012, Kim et al Cell Host Microbe 2018
1 2 3
Immune response and memory
⚫ Induration is caused by inflammation and T cell infiltration
⚫ Example of delayed type hypersensitivity response
⚫ Indicates active or latent TB
Indicates that there are large number of
Mantoux (TST Tuberculin skin test)
0 hours 72 hoursAgius JEM 2009
Immune response and memory
⚫ Induration is caused by inflammation and T cell infiltration
⚫ Example of delayed type hypersensitivity response
⚫ Indicates active or latent TB
⚫ Indicates that there are large number of circulating memory T cells specific for tuberculin
Mantoux (TST Tuberculin skin test)
0 hours 72 hours
Immunological memory depends on cell expansion and number and type of cells at the site
Agius JEM 2009
Kinetics of adaptive immunity
Lymphocytes arise from bone marrow
T cells
B cells
Lymphocytes arise from bone marrow
T cells
B cells
Generation ofDiversity, delete self reactivity
IgM/D BCR
αβ γδ TCR
Lymphocytes arise from bone marrow
T cells
B cells
Clonal selectionAdaptive immunity
Class switchingAfinity maturation
Antigen driven
selection
T cell recirculation and resident memory
⚫ T cells only transiently in blood
⚫ Normally reside in tissue, and secondary lymphoid organs
⚫ Specific cells localize in specific sites and lymphoid tissue
⚫ Population of memory cells that remain in tissues represent TRM
Schenkel Immunity 2014
1. DC critical for neo-antigen response in naive T cells
• Transport antigen to draining lymph node to initiate an immune response
• Needs to determine if the antigen is “dangerous”
2. Lymphocyte migration depends on
• Selectins (CD62L is a marker of naive T and memory T cells)
• Beta integrins (LFA1 aLb2, a4,b1, a4b7)
• Addressins
• Chemokines
Migration and Dendritic cells resolve the problem of naive T cells only in lymph nodes
Control of cell migration
Proudfoot Pharmaceuticals 2017
Control of cell migration
Byrareddy Science 2016, Arthos Curr HIV/AIDS reports 2018
Immune responses can be modulated by control of migration. CCR5 receptor blocker Maraviroc, Vedolizumab antibody to integrin α4β7 expressed on gut homing cells IBD and SIV
Proudfoot Pharmaceuticals 2017
CCR6CCR7
Circulating T cells in lymph nodes
Follicles and germinal centersB cells
Parafollicular area T cells
Medullary areaPlasma cells
Circulating T cells in lymph nodes
LN structure
⚫ Fibroblastic reticular cells (FRC) forms a reticulin network that supports the LN structure. Abnormal in HIV
⚫ T cells that facilitate antibody production localize in follicles Tfh. Target for HIV
⚫ Interdigitating DC in the paracortical T cell areas
Estes Immunol Rev 2013, Estes Semin Immunol 2008, Estes J Infect Dis 2008, Estes J Infect D 2015, Banga Nat Med 2016, Banga Front Immunol 2018
DC heterogeneity and specific functions
Schultze et al Sem Cell and Develop Biol 2018
Antiviral Immunity
IFN
DC processing presentation and sensing “signal 0”
Yatim Nat Rev Immunol 2017
Adaptive immunity; T cell development is controlled by cytokines and nuclear transcription factors
1.Development of adaptive immunity absolutely depends on signalling through specific antigen receptors
TcR signalling for T cells
BcR (IgM/D) for B cells
2.The cytokine environment acting through specific interleukin receptors and cell intrinsic nuclear factors determines phenotype
3.Effector function depends on location (chemokine receptors) and production of cytokines
Adaptive immunity; T cell development is controlled by cytokines and nuclear transcription factors
Adaptive immunity; T cell development is controlled by cytokines and nuclear transcription factors
Adaptive immunity; T cell development is controlled by cytokines and nuclear transcription factors
Adaptive immunity; T cell development is controlled by cytokines and nuclear transcription factors
Adaptive immunity; T cell development is controlled by cytokines and nuclear transcription factors
Development of T cell phenotypes
What is the source of the cytokines that drive the differentiation of T cells?
Innate immunity. Parallel development of innate lymphoid cells ILC and adaptive lymphoid cells.
Mucosal Immunology (2016) 9, 1103-1112
Adaptive Innate Cytokine, function
Th1 ILC1 IFNγ, TNFα
Virus Mycobact Intra cellular microbes
Th2 ILC2 IL5, IL13, IL4
Allergy Helminth
TH17 ILC3 IL17 IL-22
Mucosal immunity
Unlike adaptive T cells the ILC are not dependent on modified TcR for their development
Innate immunity. Sensing and responding to infections.
Rivera et al Nat Immunol 2016
Annals of the New York Academy of Sciences
Volume 1356, Issue 1, pages 1-21, 30 APR 2015 DOI: 10.1111/nyas.12763
http://onlinelibrary.wiley.com/doi/10.1111/nyas.12763/full#nyas12763-fig-0001
Innate immunity. TLR and Interferon system.
IRF3 → type I IFN production
Surface TLR (alarmins “damaged self” and bacterial pathogens)
Endosomal TLR (viral pathogens)
Chow et al Virology 2015
Innate immunity. Intra cellular receptors for detection of viral RNA and DNA
RLR = Rig-I like
Receptor
IFNs are critical downstream mediators of protection from TLR and viral sensing
Innate immunity and unconventional T cells
− Innate responses provide immediate protection.
− Not true innate memory but innate cells can expand and are associated with enhanced responses “Trained innate immunity”1.
− Occurs in both myeloid cells and NK cells2
Godfrey Nat Immunol 2015 1Saeed et al Science 2014, 2Cerwenka et al Nat Rev Immunol 2016,
Innate lymphoid cells and innate sensing
Unconventional T cells including MAIT cells can sense small molecules from bacteria virus and tissue damage. Provide initial priming for conventional T cells. Add to complement, CLR, TLR, natural Ab and defensins. Godfrey Nat Immunol
2015
Resolution of immune responses
− Why the decline in cell numbers after the response?
⚫ Cell death by apoptosis
⚫ Reduced expansion negative regulators or immune checkpoints
⚫ Change in phenotype. Conversion of effector cells to memory cells.
Cell death and
Immunity
⚫ Apoptosis
⚫ Necrosis
⚫ Necroptosis
⚫ Pyroptosis
Negative regulation and control of the immune response
⚫ Self and non-self recognition in the humoral immune responses
− Complement and regulators of complement activation
⚫ classical complement activation
⚫ Alternative pathway of activation
⚫ Lectin pathway of activation MBL
⚫ Absence of regulators associated with complement activation
⚫ NK cell activation
⚫ Activating receptors
⚫ KIR Inhibitory receptors absence of ligand for inhibitory receptors results in activation
⚫ Class I is ligand for KIR
Lack of self can be the basis of recognition of pathogens
Costimulation, and immune checkpoints
Wykes and Lewin Nat Rev Immunol 2018
Immune checkpoints in HIV infection
Wykes and Lewin Nat Rev Immunol 2018, Evans AIDS 2018,
Chomont Nat Med 2009, Fromontin Plos Pathogen 2016
Components of immunity
⚫ Antigen uptake and processing Vaccination strategies
⚫ Generation of memory cells Cytokines
⚫ Regulation of immune responses Immune checkpoints
⚫ Generation of antibody responses Broadly neutralizing antibodies
⚫ Recognition of foreign pathogens Toll receptors and IC sensing
⚫ Unconventional T cells Vaccine adjuvants
⚫ Effector immune responses
− Cytotoxic T cells
⚫ NK and CTL cytokines IL15, CAR-T-cells
− Macrophages and Phagocytic cells ADCC
⚫ ADCC, complement and antibody broadly neutralizing antibodies
⚫ Killing (apoptosis, necrosis and pyroptosis) IFN, SMAC mimetics
Immunotherapy in HIV
Deeks nature 2012, Kim et al Cell Host Microbe 2018
1 2 3
TLR 7, 9 agonist
IFN
SMAC mimetics
Immune checkpoint Blockers PD1, CTLA4
Vaccination DNA
Viral vectorsDC Adjuvants non-conventional T cells
Cytokines IL-15