TLR2 stimulation facilitates integration within naive and memory CD4 T cells

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Sandra Thibault MSc
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Microbial translocation

• Phenomenon observed in HIV-infected individuals
• Presence of bacterial products in bloodstream
• Results from damage of the mucosal barrier in the
  gut
• Important cause of the systemic immune activation

3
HIV-associated Immune activation increases the
pool of target T cells

• Effector CD4 T cells are the main target cells
• HIV-associated immune activation results in
  abnormal accumulation of effector CD4 T cells in
  lymph nodes

4
CD4 T cells sense microbial products through
various TLRs

• TLRs recognizing pathogens associated molecular
  patterns (PAMPs)
• Bacterial products TLR2, TLR4, TLR5, TLR9
• Viral products TLR3, TLR7/8
• Ligand binding to TLR triggers signaling cascade

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CD4 T cells sense microbial products through
various TLRs (2)

• T cells express numerousTLRs including TLR2
• Effector and central memory T cells express more
  TLR2 than naïve ones
• Bacterial products TLR T cell activation

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Naïve and central memory CD4 T cells become
effector like in response to TLR2L

• Naïve and memory cells clustered following TLRs
  stimulation
• Activation markers were expressed on both
  subtypes (CD69, CD25, HLA-DR, ICAM-1, CCR5)

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TLR2 stimulation renders naïve and memory CD4 T
cells more susceptible to HIV-1 infection
Naïve
Memory
Thibault S., Journal of Immunology Oct 2007
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What HIV life cycle step is favored when resting
T cell subsets are stimulated with TLR2L?
www.dharmacon.com
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Entry of HIV-1 was not modulated following TLR2
stimulation
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Reverse transcription is enhanced in
TLR2-stimulated naïve and central memory CD4 T
cells
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TLR2 stimulation increases the amount of
integrated proviral DNA in both naïve and memory
T cells
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TLR2 stimulation induces activation of NF-kB
in both T cell subsets
Thibault S., Journal of Immunology, Oct 2007
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Conclusions
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Conclusions (2)

• TLR2 stimulation is sufficient to remove
  post-entry restrictions in both naïve and
  central memory T cells
• The impact is more pronounced with memory cells
• HIV-1 propagation is facilitates due to an
  increase of activated cells

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Acknowledgments
My director Michel J. Tremblay My leader
project Mélanie R. Tardif Rémi Fromentin MSc
Project leaders Postdocs MSc
students Réjean Cantin PhD Ravendra Garg Diane
Malaison Corinne Barat PhD Pranav Kumar Audrey
Plante Michel Ouellet PhD Alexis
Danylo Robert Lodge PhD PhD students Katia
Giguère Simon Mercier Technical
assistants Jonathan Bertin Marc-André
Côté Alexandra Lambert Caroline Côté Sonia
Gauthier Nathalie Trudel Michaël
Imbeault Renaud Tremblay Juliette
Diou Lise-Andrée Gobeil
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TLR2 stimulation increases the amount of
integrated proviral DNA in both naïve and memory
T cells
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www.iavireport.org/Issues/Issue9-2/GuardianOfTheGe
nome.org
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Naïve and memory CD4 T cells

• Circulating cells in contact with free viruses
• Very different (chemokine receptors,
  transcription factors, activation state)
• Weakly permissive to productive infection