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“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