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Dissecting T cell responsiveness to C- cytokines in HIV-infected subjects

NICD. CAPT Network African Led, Canadian Enabled. Dissecting T cell responsiveness to C- cytokines in HIV-infected subjects. Catherine Riou NICD/PHRU Johannesburg, South Africa. How different T cell subsets respond to cytokines?

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Dissecting T cell responsiveness to C- cytokines in HIV-infected subjects

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  1. NICD CAPT Network African Led, Canadian Enabled Dissecting T cell responsiveness to C-cytokines in HIV-infected subjects Catherine Riou NICD/PHRU Johannesburg, South Africa

  2. How different T cell subsets respond to cytokines? Is cytokine responsiveness impaired in HIV-infected individuals? Do specific profiles of T cells associate with viral control? Background • Cytokines play a key role in the proliferation, differentiation, function and survival of T cells. • HIV-specific cells are defective in their ability to proliferate and to produce cytokines.  Less is known about T cell responsiveness to cytokine in HIV + individuals.

  3. AIMS • Study the phosphorylation profiles of different T-cell subsets in response to exogenous c-cytokine engagement • IL-2 : T cell proliferation and activated induced cell death (AICD) • IL-7 and IL-15 : maintenance of T cells (IL-15 favours the cell proliferation and IL-7 rather favours cell survival). • Study the phosphorylation profiles of HIV- and CMV-specific CD8+ T cells in response to exogenous c- cytokine triggering.

  4. r=-0.57 p<0.0001 1200 800 800 700 600 500 400 400 300 200 200 100 0 10 2 10 3 10 4 10 5 10 6 Viral load Study Subjects 18 HIV-discordant couples HIV+ individuals present different rate of disease progression

  5. Studied Pathways c-Cytokine triggering (IL-2, IL7, IL15) No stimulation +IL-7 (15min) Cell count Phospho-Stat5 Proliferation Survival

  6. Studied T cell Subsets Naïve and Memory subsets

  7. Differentiation lineage Central Memory Transitional Memory Effector Memory Naïve Effectors proliferation Maturation Survival Burgers, Riou et al. JI. 2009

  8. Cytokine responsiveness in HIV- individuals HIV uninfected individuals IL-2 IL-7 Phospho Stat-5 (%) N CM TM EM Eff N CM TM EM Eff Phospho Stat-5 (%) CD8+ CD4+ IL-15 Phospho Stat-5 (%) N N CM TM EM CM TM EM Eff Eff CD4+ CD8+ N CM TM EM Eff N CM TM EM Eff CD8+ CD4+ • T cells responsiveness to cytokines decreases with Cell differentiation (CM>TM>EM>Eff) in both CD4 and CD8 compartments. • Naïve cells are characterized by a diminished responsiveness to IL-15 and IL-2

  9. Cytokine responsiveness in HIV+ vs HIV- individuals IL-7 HIV+ CD8+ cells HIV- pSTAT-5 (%) - + - - - HIV + + - + + N CM TM EM Eff No major differences in cytokine responsiveness between HIV+ and HIV- in any CD8+ T cells subsets

  10. Correlation % IL7-R and Stat-5 response pStat-5 expression (%) p=0.0002 (***) p=NS IL7R expression (%) Dose response IL-7 pStat-5 expression (%)  Dissociation of Receptor expression and IL-7 responsiveness in HIV+ Individuals. IL-7 concentration (ng/ml) • IL-7 Receptor levels do not reflect responsiveness in HIV-infected individuals. Relationship between Receptor Expression and Cell Responsiveness IL-7 Receptor expression levels *** *** * CD127 expression (%) HIV+ HIV- - - - - - + + + + + N EM CM TM Eff

  11. pSTAT-5 pSTAT-5 T cell responsiveness to cytokines in Antigen-specific T cells HIV and CMV Co-infected donors with undetectable Viral Load CMV (A2-pp65) HIV (A2-Gag) Total CD8+ TET+ cells Total CD8+ TET+ cells 61% 81% 64% 82% SSC IL-7 0.9% TET-PE We can speculate that HIV-specific cells in controllers present a Early-Differentiated phenotype according to their high responsiveness to IL-7.  Which HIV-specific T cells subsets associate with viral control ? p-Stat5 (%) CD8 Total CMV spe HIV spe

  12. Which HIV-specific CD8+ T cells subsets associate with viral control? % of Central Memory % Effector Memory p=0.002 r = -0.54 p=0.0009 r = 0.58 Burgers, Riou et al. 2009 Viral set point at 12 months +IL-7 P-Stat-5 Accumulation of Early differentiated cells at 6 months correlate with low viral sets point at 12 months

  13. Conclusions • HIV infection does not to alter the capacity of T cells to respond to IL-2, IL-7 and IL-15. • T cell memory subsets show distinct phosphorylation profiles in response to exogenous cytokine stimulation: cells heading for terminal memory differentiation lose the ability to respond to IL-7. • EM CD8+ T cells positively correlate with high viraemia • Maintenance of CM early differentiated CD8+ T cells associates with viral control. Hypothesis: early differentiated T cells capable of responding to cytokine signaling are important for controlling HIV in the absence of ARV therapy

  14. Potential model for Viral Control Low Viral set point High Viral set point EM EM CM CM • High responsiveness to cytokines • Good proliferation capacities • Good survival abilities • Low responsiveness to cytokines • Low proliferation capacities • Low survival abilities Desirable from a vaccine

  15. NICD CAPT Network African Led, Canadian Enabled NICD, Johannesburg Netty Malatsi Pr. Clive Gray Funders PHRU, Soweto CAPT CHAVI Bara Clinical Team Dr. Guy de Bruyn University of Montreal Pr. R.P. Sekaly

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