Immune memory

—> local infection, penetration of epithelium (wound healing induced, antimicrobial proteins & peptides, phagocytes & complement destroy invading microorganisms)

—>local infection of tissues (complement activation, DC migration to lymph nodes, phagocyte action, NK cells activated, cytokines & chemokines produced)

—>lymphatic spread (pathogens trapped & phagocytosed in lymphoid tissue, adaptive immunity initiated by migration of DC)

—>adaptive immunity (infection cleared by specific Ab, T-cell-dependent macrophage activation & cytotoxic T-cells)

adaptive immune response only triggered over a certain level of antigen

establishment of infection —> inductive phase —> effector phase —> memory phase

the peak of the pathogen before activation of the adaptive immune response, then clearing

most antigen-specific lymphocytes die when no pathogen can be detected anymore

some maintained to constitute the memory

allows quicker and more efficient response to the second infection

quicker: more precursors of antigen-presenting cells than initially

more efficient: increased affinity & class switch in the first reaction

between the responses a small amount of Ab in the serum

second response main reason for booster injection after initial vaccination

dependent on IL-7R

naive T-cells require signals from contact with self-peptide: self MHC complexes & cytokines IL-15 & IL-17 for survival —>positive selection of self-peptide: MHC interaction & cytokines deliver survival signal

native T-cell encounters an antigen

—>most activated T-cells become effector cells

—>some activated and/or effector cells become long-lived memory cells (maintain IL-7R)

cytokine-dependent (IL-7) & less dependent on continuous TCR stimulation (self-peptide/ MHC interaction)

mice infected with LCMV generate primary CD8 response, some effector cells express high levels of IL-7R while others don’t

use TCR transgenic mice: 1 α & ß-chain —> block endogenous TCR rearrangement (only 1 T-cell clone expressed)

purify CD8 cells at peak of the response & sort according to IL-7R expression

—>only transfer IL-7Rα hi CD8 T-cells into naive mice led to robust expansion of antigen-specific CD8 cells after secondary challenge

—> Quantify antigen-specific T-cells via fluorescent antigen staining & flow cytometry

MHC + peptide coupled to fluorophore/biotin —> soluble

use tetramer for sufficient affinity (formed via avidin/biotin interaction)

1 streptavidin binds 4 biotin (streptavidin labeled)

memory pathway IL-7R+ & CD45RO (active in naive CD45RA)

central memory cells express CCR7 & remain in lymphoid tissue

effector memory cells lack CCR7 & migrate to tissues —>2 subsets of memory cells

marker for different T-lymphocyte states allows the following immune response

—>changes in adhesion molecules, interaction with APC, chemokine receptors, survival signaling & effector function

adhesion molecule on activated T-cells (effector & memory)

in activated T-cells modulating TCR signaling (effector & memory)

downregulated in effector cells, upregulated in memory & naive T-cells

L-selectin for homing to lymph nodes

not in effector T-cells & effector memory cells (reside in tissue)

chemokine receptor for homing in lymph node

present in native and central memory cells

early activation antigen only on effector T-cells (transient activation antigen)

promotes cell survival in memory & naive cells, almost lost in effector cells (die after clearance)

effector cytokine, also in memory cells in granules —> for quick response & effector cells

effector molecules in cell killing mostly in effector, minimal in memory

part of receptor for IL-2 & transiently expressed in effector T-cell

part of the receptor for IL-7 in memory & naive T-cells

receptor for chemokines CCL3 & CCL4 —>tissue migration

absent in naive & central memory

WT mice & mice lacking MHCII infected with LM bacterium expressing an ovalbumin antigen

after 7 days both types have expanded a similar number of OVA-specific CD8+ T-cells

after 70 days rechallenged —> only WT mice can expand OVA-specific memory cells

—> no memory/no-reexpression: memory CD8 T-cells w/o CD4 T-cells not generated/die

other experiment: memory CD8 T-cells develop in mice infected with LCMV

LCMV-specific CD8 memory T-cells are transferred into WT or mice lacking CD4 T-cells (MHCII KO)

—>memory CD8 T-cells maintained in mice with CD4 T-cells but not in mice lacking CD4 T-cells

—>dependent on CD40 for survival of memory CD8 T-cells —> needed for maintenance

IgG mainly in memory response —> has a much higher affinity

—> affinity & amount of Ab increase with repeated immunization

affinity increase of around 1 million-fold from the initial level of the specific IgG

individual (2 years) infected with influenza virus makes Ab against all epitopes present on the virus

same individual (5 years) infected with influenza variant —> makes only Ab against shared epitopes with the original virus (memory antigen-specific, no response to new epitopes)

infection with new variant —> only Ab against epitopes shared with the individual virus not against shared epitopes with the variant encountered before

—>first encountered antigens rule the memory generation & subnormal response to new epitopes

leads to faster & more efficient response

somatic hypermutations in variable regions for increased affinity

after smallpox vaccination Ab levels without significant decline & T-cell memory show a half-life of 8-15 years

Ab: still high after 30 years, huge memory —> long-lived plasma cells (differentiated B-cells in the bone marrow)

CD4 & CD8 T-cell memory is long-lived but gradually decays

no complete contraction

contraction = dying of effector cells after clearance of the pathogen

the number of virus-specific NK cells don’t decline to level before infection but a memory to a much lesser extend

UK farmer inoculated family members with fluids from cowpox lesions during severe smallpox outbreak

—>person having contracted cowpox not infected by human smallpox assumed among farmers (1774)

Edward Jenner conducted 1st human to human trial (variolation)

injection of a small amount of dried fluids from a patient suffering from a mild disease —> success but 3% of fatal smallpox disease (afterward injection of cowpox)

nowadays the vaccine is the vaccinia virus ( also from the poxvirus family)

smallpox vaccination the most successful vaccination —>officially eradicated in 1977

1885

made a vaccine against rabies with an in vitro inactivated strain of the virus

Inactivates viruses: killed by heat/ fixation —>don’t infect host cells, no CD8+ T-cell response, Abs & CD4+ T-cells produced

Attenuated viruses: Abs, CD4 & CD8 T-cells produced —>can infect cells

synthetic vaccines: recombinant proteins/peptides associated to an adjuvant (epitopes for T-& B-cells)

triggers immune response & interacts with the inflammasome

hydroxyl-aluminium only adjuvant used in humans

—> increases stability of the antigen (oil elucifies Ag, creates depot at the site of injection leading to slow release of Ag after injection)

—> increases immune response

—> provides signal 2 to specific T-cells (need PRR ligand)

antigenic variation —> annual design of a killed virus vaccine

moderately effective reducing mortality in elderly & illness in adults (40%)

ideal vaccine = live attenuated vaccine matching the season strain

solution for improvement: universal flu vaccine with broadly neutralizing Abs

attenuated vaccine from a pathogenic isolate of Mycobacterium bovis passaged in the lab

variable effects: none in some countries (Malawi) to 50-80% in the UK —> MHC polymorphism

optimization required = recombinant BCG vaccines, overexpression of the immunodominant antigen of the human Mycobacterium tuberculosis

Moderna & BioNTech: muscle injection of the mRNA of the spike from SARS-CoV2 encapsulated in liposomes

Astrazeneca/J&J/Spoutnik: replicative-deficient adenovirus from monkey encoding for the spike (intramuscular)

hinders herd vaccination but herd immunity needed to protect people not responding to vaccines

autism & Mumps-Measles-Rubella vaccines: hypothesized from Dr. Wakefield led to insufficient MMR immunization coverage rates in the UK, triggering measles outbreak

today paper retracted—>guilty of ethical, medical & scientific misconduct

additional studies showed that the data was fraudulent

no link demonstrated between risk of developing multiple sclerosis & vaccination