AMI - Lecture 3 - Dendritic cells in tailored adaptive immunity

3 main phases initiated when first infected with a pathogen

• innate (0-4 hours) → complement activation

  • anaphylatoxins (C3a → increased vascular permeability, leukocyte, neutrophils, recruitment)

  • opsonization (C3b → enhanced phagocytosis)

  • Membrane attack complex formed

• early induced innate response (4-96 hours) → phagocytosis happens

• adaptive (>96 hours) → DCs activate adaptive immune system. macrophages pahgocytose + interact with T cells.

Phagocytosis

MQ + DC use pathogen recognition receptors to recpognize

• PAMP (pathogen)

• DAMP (danger)

• SAMP (self)

difference between naive and effector T and B cells

• Naive T → immature waiting to be activated,

• effector T → activated + differentiated, T helper subsets, have undergone clonal expansion, short lived or turn into memory T cells

• Naive B → resting, circulating through body looking for ag. typically IgM

• effector B → activated, have encountered specific ag, have proliferated + differentiation, memory B cells or plasma cells, there have been isotype switching

3 signals required for T cell activation

• ag presentation → MHC1 - CD8, MHC2 - CD4

• co stimulation → CD28-CD86 → proliferation

• cytokines secretion by APCs → T helper cell differentiation

C type lectin receptors

• expressed at cell surface of immune cells → important for phagocytosing

• ag uptake, presentation, signalling

• carbohydrate recognition domain (CRD) → bind carbohydrate structures

• CLR have intracellular signalling motifs → will lead to

  • maturation of dendritic cells,

  • cytokine production,

  • type 1 interferon activation,

Toll like receptor

• recognize pathogens via PAMP

• found on cell surface and intracellular on endosomes

• activation results in cytokine secretion by DCs

• IRF 3/7 are activated leading to type 1 interferon production

NOD like receptor

• inside cytoplasm

• detects intracellular bacteria + cell wall damage

• detects bacterial DAMPs + PAMPs

• activates NfKb pathway → important of IL1 production

RIG like receptor

• inside cytosol

• detect viral RNA

• activate type 1 interferon

• signalling happens via RIG1 (ssRNA) + MDA5 (dsRNA) → then activation IRF3 → type 1 interferon production

inflammatory cytokines

• signaling molecules that are produced by immune cells (MQ, DCs) in response to infection

• these cytokines coordinate immune responses through NF-kB

• NF-kB (transcription factor) activated by; inflammatory cytokines, PAMPs, ROS → promote expression of genes encoding for pro-inflammatory cytokines

  • IL4, IL6, IL12, TNFalpha, TNFbeta

Type 1 interferons

• viral infection

• IRF3/7 are the transcription factors activated in response to viral RNA/DNA → once activated IRF3/7 translocated to nucleus → induce transcription type 1 interferons (IFNalpha, IFNbeta) → block viral replication, degrade viral RNA

IL1 family

• these cytokines are released in response to intracellular infections

• inflammasome activates cytokines (IL1)

• IL1alpha, ILbeta, IL18

TLR signalling via My88 and TRIF

• My88 → signalling molecule

  • pathogen binds TLR → My88 recruits kinases → activation of NF-Kb → production pro inflammatory cytokines

• TRIF → signalling molecule

  • pathogen binds TLR → TRIF recruits kinases → activation of IRF3/7 and NF-Kb → production of type 1 IFN + pro inflammatory cytokines

• REMEMBER; NF-Kb pro inflammatory, IRF interferon 1

• TLR can induce both, depending on which ones are activated

2 step IL1 cytokine production

• DC needs two steps before it can start producing IL1 cytokines

• priming transcriptional activation;

  • NOD like receptors are important → recognize PAMP → NF-Kb activated → NF-Kb translocates to nucleus → induces expression of pro IL-1beta

• activation post translational;

  • PAMP + DAMP activated → inflammasome formation → caspase 1 activated → caspase 1 cleaves pro IL-1beta into active form

• IL1 is crucial in inflammatory response → enhances proliferation and differentiation of T cells. Promotes CD4 and specifically TH17

Cross presentation route

• cross over is between exogenous (MHC2 + CD4) and endogenous (MHC1 + CD8)

• effect; exogenous ag expressed on MHC1

  • crucial for initiating cytotoxic T cell responses against viruses, tumors, or pathogens that do not infect (APCs) directly

• TLR4 enhances cross presentation

• depending on which PRR are activated will have an effect on all the signals of DC

  • can enhance specific T helper cell responses

  • inhibit signalling cascades to change ag handling and cytokines responses

• intracellular signalling cascades can cross talk → can induce synergy and cross inhibition

2 things a vaccine always needs

• antigen → immune system will recognize this as foreign substance

• adjuvant → immune stimulating substance, enhances body’s immune respons to ag. will activate DC and PRR

what do tumour vaccines induce

• cytotoxic T cell responses

  • cross presentation of ag is needed for this

  • mature DCs needed → provide all 3 signals

  • CD4 + Th1 cells are needed to help the memory response of CD8 cells

  • CTL receptors needed to enhance cross presentation

why is intradermal vaccination often used

• skin is rich in DCs

• skin highly vascularized by blood and lymphatics. will facilitate transport of immune cells + ag to lymph nodes where adaptive immunity is activated

• easy accesible

Why are cytotoxic T lymphocytes often used in anti tumor vaccination

• want a long lasting cytotoxic T cell response

• optimal CTL response requires;

  • ag cross presentation

  • mature DC to provide signal 1-2-3

  • CD4 T helper help