adaptive immune response to protozoan pathogens

Question 1

T cells

Answer 1

• key in adaptive response to parasites
• increased parasitaemia and death in T cell deprived (nude) mice
  
  • T. cruzi, T. gondii, P. yoelii (mouse malaria)
• nude = no thymus from FOXN1 gene deletion
• supplementing T cells rescues immune response in T. cruzi

Question 2

cross talk between innate and adapvtive immunity

Answer 2

• T cells activated by APCs
• antigen presentation on MHC
• CD4+ - class II
• CD8+ - class I

Question 3

CD4+ T cells

Answer 3

• form T helper cells upon activation
• TH1 - pro-infalmmatory environment
  
  • IFN, IL-2 and T-bet TF
• TH2 - anti-inflammatory environemnt
  
  • IL-4, IL-10 and GATA-3 TF

Question 4

role of DCs in adaptive immunity

Answer 4

• APCs - required for development of T cell response to protozoa
• present antigen to naive T/B cell
  
  • stimulates clonal expansion and differentiation
  • B cells produce antibodies
• variability in APCs produces different responses
  
  • depends on receptor and cytokine expression

Question 5

B/T cell contraction

Answer 5

• after infection has been eliminated B/T cells die by apoptosis
• some T cells remain as memory cells with IL-7 receptors

Question 6

DC depleted mice

Answer 6

• diphtheria toxin injected to deplete DCs
• impaired T cell response to malaria

Question 7

DCs in T. gondii infection

Answer 7

• potential source of IL-12
• Batf3 knockout mice lack some DC populations
• die upon T. gondii infection
• rescued by treatment with IL-12
• IL-12 activates CD8+ T cells and NK cells

Question 8

extracellular antigen presentation

Answer 8

• on MHC II
• CD4+ helper T cell activation
  
  • cytokines and parasite killing by macrophage activation
• B cell binding to antigen and presentation to helper T cells
  
  • antibody production by B cell

Question 9

cytosolic antigen presentation

Answer 9

• on MHC I
  
  • on almost all nucleated cells
  • incorrect expression indicates something wrong with cell
• presented to CD8+ cytotoxic T cells
• direct killing of APC

Question 10

CD8+ cells and malaria

Answer 10

• CD8+ key during liver stage
  
  • create series of clones produced specific to sporozoite molecules
  • transfer clones adn see protection
  • different clones confer different levels of protection
  • non-specific clones → no protection

Question 11

CD4+ cells and malaria

Answer 11

• key during blood stage
• depletion of CD4 increases suceptibility
  
  • depletion of CD8 does not
  • CD8 can’t recognise RBCs (no MHC I)

Question 12

CD8+ T cells and cerebral malaria

Answer 12

• P. berghei variant causing cerebral malaria
• myeloid APC in contact with CD8 cells for longer time than with variant that produces non-cerebral malaria
• CD8+ cells accumulate in brain in both infections however

Question 13

role of CD8+ T cells

Answer 13

• generally to kill infected cells that can’t kill parasite themselves
  
  • hepatocytes in malaria liver stage
  • other nucleated cells in T. gondii and T. cruzi
• also IFN production to stimualte other cells

Question 14

macrophage activation by CD4+ T cells

Answer 14

• requires CD40 ligation for effective intracellular parasite killing
  
  • e.g. T. gondii

Question 15

CD4+ T cell polarisation

Answer 15

• determines protective capacity during infection
• depnds on environment
• TH1
  
  • in presence of IFN, leading to IFN production
  • pro-inflammatory
• TH2
  
  • in presence of IL-4, leading to IL-4 production
  • anti-inflammatory

Question 16

pro-inflammatory response

Answer 16

• regulation needed to prevent immunopathology
• IL-10 - classic regulatory cytokine

Question 17

IL-10

Answer 17

• regulatory cytokine (anti-inflammatory)
• inhibits activity of Th1, NK cells and macrophages
• prevents immunopathology
• knockout IL-10 mice - increased parasitaemia
• increased IL-10 - necrotic areas in liver

Question 18

the fourth dimension

Answer 18

• metabolism drives the life cycle of T cells
• naive T cells highly reliant on oxidative phosphorylation
• higher energetic demand once activated
  
  • increased dependence on glycolysis
• T cells sense metabolic environment and react accordingly using mTOR

Question 19

mTOR pathway

Answer 19

• mTOR - mammalian target of rapamycin - kinase
  
  • signalling node
• critical pathway activated in T cells once they become glycolytic (activated by antigen)
• regulated by other pathways e.g. AKT
• cue integration by mTOR from immune microenvironment guides T cell fate decisions
  
  • crosstalk between immunological and metabolic signalling programs
  • contradictory findings

Question 20

evidenc for mTOR involvement

Answer 20

• mTORc1 blockade in macrophages
  
  • increased IL-12, decreased IL-10 in Leishmania infection
• mTORc2 targeting by T. gondii can limit host cell mobility to prevent spread of infection
• dietary restriction reduces mTORc1 activity in T cells during malrai infection
  
  • block with rapamycin to prevent cerebral malaria pathology

Question 21

mTOR in malaria infection

Answer 21

• effector T cells governed by metabolism
  
  • controlled by mTOR integrative signalling node
  • infection outcome controlled by patways modifying mTOR and metabolism
  • certain T cell events correlate with mTOR changes

Question 22

role of B cells

Answer 22

• antibody production
  
  • more important with extracellular parasites - T. brucei
• can limit spread of intracellular parasites in macrophages

Question 23

antibody mechanisms

Answer 23

• direct damage to parasite
  
  • membrane disruption by complement-mediated lysis (Plasmodium)
• parasite opsonisation
  
  • neutralises attachment sites to prevent spread
  • prevent lysosomal vacuole escape or inhibition of fusion
  • more effective if C3b and antibody bound
• enhance phagocytosis
  
  • adaptor between phagocyte and parasite

Question 24

control of malaria by antibodies

Answer 24

• complement activated leading to lysis by MAC
  
  • membrane disruption and fluid leakage
• invasion inhibition