t follicular helper cells in hiv infection
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T follicular helper cells in HIV infection. Jan van Lunzen University Medical Center Hamburg-Eppendorf Heinrich-Pette-Institut for Experimental Virology & Immunology Hamburg, Germany. Outline/Questions. Where does HIV replicate in LN? Which cells are preferentially infected? - PowerPoint PPT PresentationTRANSCRIPT
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T follicular helper cells in HIV infection
Jan van LunzenUniversity Medical Center Hamburg-Eppendorf
Heinrich-Pette-Institut for Experimental Virology & ImmunologyHamburg, Germany
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Outline/Questions
Where does HIV replicate in LN? Which cells are preferentially infected? What effect/limitations does HAART have? What is the role of T follicular helper cells in HIV
infection? Are TFH cells a viral reservoir? What are the consequences of dysregulated TFH
function? Can these functions be restored?
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Where does HIV replicate in lymph nodes?
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Lymph Node PathologyHIV - HIV +
Stellbrink & van Lunzen, Curr Opin Infect Dis 2001
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Immunopathology of LN
Tenner-Racz K, Stellbrink HJ, van Lunzen J et al., J Exp Med 1998
CD4+Ki-67+
CD8+
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Which cells are preferentially infected?
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Infection rate of CD57+ and CD57- CD4+ T cells in PB and LN
10
7,5
5
2,5
01 2 3 5 7Patient no.
Infe
cted
cel
ls (%
)
LN CD57+CD4+ T cellsLN CD57–CD4+ T cells
PBL CD57+CD4+ T cellsPBL CD57–CD4+ T cells
Ratio of the viral loads: CD57+CD4+ T cells [%]/CD57– CD4+ T cells [%]
LN: 10.5 3.3 8.0 9.5 3.0PBL: 0.3 2.2 <0.1 2.5 2.5
Hufert F, van Lunzen J et al.: AIDS 1997
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What effect/limitations does HAART have?
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HIV-1 RNA in LN during HAART
Tenner-Racz K, Stellbrink HJ, van Lunzen J et al., J Exp Med 1998van Lunzen J, Ruiz L et al., AIDS 1998
Day 0 Day 28
HIV-1 RNA p24 Ag
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T cell proliferation in LN during HAART
15%
10%
5%
0CD4+Ki-67+ CD8+Ki-67+
p < 0,0001
p < 0,0001pre-treatment (n = 30)post-treatment (n = 30)normal controls (n = 4)
van Lunzen J, et al., CROI 1999
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What is the role of T follicular helper cells in HIV infection?
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CD4 TFH cells B cell
MHC IITCR
IL-21 IFNγIL-4
• B cell proliferation• Antibody maturation (SHM)• Class switching (CSR)• Memory development
• Within the follicle• Express CXCR5, PD1, ICOS• Bcl6+ • IL-21 (cardinal cytokine)
Plasma cell
Memory B cellCD40L CD40
CD4 TFH cells are critical for effective antibody responses
Bcl6
CXCR5
ICOS ICOSLBcl6
PD-1
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SIV: Relative Accumulation of TFH in LN SIV acute SIV chronic (high % of TFH)SIV- SIV chronic (low % of TFH)
% o
f CM
CD
4 T
cells
p=0.0008 p<0.0001
PD-1
CC
R7
0 103 104 1050
102
103
104
105
ICO
S
CD150 Petrovas C. et al. JCI 2012
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PD-1
CC
R7
Immune activation rather than direct infection with SIV is associated with in vivo TFH accumulation
0
0.5
1.0
1.5
Chronic SIV (>2 months)
SIV
Gag
DN
A (c
opie
s/ce
ll)
0 103 104 1050
102
103
104
105
ICO
S
CD150
p=0.0013p=0.0004
p=0.0164
sCD
14 (x
106 p
g/m
l)
SIV acute SIV chronic (high % of TFH)SIV- SIV chronic (low % of TFH)
Petrovas C. et al. JCI 2012
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Accumulation of TFH is Associated with Increased Frequency of GC-B cells and titers of SIV-specific
Antibodies
PNAhighIgGlow
PNAhighIgGhigh
SIV - SIV +low % TFH
SIV +high % TFH
p=0.0286
SIV-
spec
ific
IgG
(ti
ter,
x104 )
p=0.051
p=0.033p=0.048
ND
ND
ND
ND
ND
0
2.5
5
7.5
10
SIV acuteSIV chronic (low % TFH)SIV chronic (high % TFH)
gp120 gp130 gp140 p27 p55
Petrovas C. et al. JCI 2012
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High frequency of CXCR5+PD-1high CD4 T cell subset in the lymph node
Lindqvist M et al., JCI 2012
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IL-21 preferentially produced by TFH cells
Lindqvist M et al., JCI 2012
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Expansion of TFH cells correlated with skewing of B cell subsets
GC B cells Late memory B cellsPlasma B cells
Lindqvist M et al., JCI 2012
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Hypersecretion of IgG was associated with BCL6 expression in TFH cells
Lindqvist M et al., JCI 2012
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Are TFH cells a viral reservoir?
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TFH Cells and CXCR5-PD-1+ CD4 T-Cells Are Enriched in HIV-Specific CD4 T-Cells
LNMCs Intracellular staining
Aqua, CD3, CD4, CD8, CD45RA, CXCR5, PD1, IL-21, IL-2, TNF-α, IFN-γ
PTEs (Gag, Pol, Env)+α-CD28Brefeldin A
Perreau M et al JEM 2012
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TFH Cells and CXCR5-PD-1+ CD4 T-Cells Are Enriched in CD4 T-Cells Containing HIV DNA
DNA extraction Taqman RT-PCR HIV-1 gag gene
Perreau M et al JEM 2012
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TFH Cells and CXCR5-PD-1+ CD4 T-Cells Are the Most Efficient in Supporting Production of HIV
p24 detection
D5D0
Anti-CD3/CD28
Collection of SNs
D2
High viremia (>15000 HIV RNA copies/mL)
Perreau M et al JEM 2012
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HIV Isolation from Patients with Low (<1000 HIV RNA copies/mL of plasma) in Different CD4
T-Cell Populations
TFH and CXCR5-PD-1+ but not CXCR5-PD-1- and CXCR5+PD-1- CD4 T-cells efficiently support virus isolation and production in patients with low viremia levels
Low viremia (<1000 HIV RNA copies/mL)
p24 detectionCoated CD3/28
CD8-depleted PBMCs+
D7D0
Collection of SNs
D3
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What are the consequences of dysregulated TFH function?
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PD-L1 expression in GC B cells
Cubas RA et al. Nature Med. 2013
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PD-1 ligand and TFH proliferation, activation and cytokine secretion
PD1-L
Cubas RA et al. Nature Med. 2013
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IL-21
pg/
ml
Unstim. IgG beads
PD-L1 beads
0
20
40
60
80
100
ICO
S M
FI
P = 0.03P = 0.01
Abso
lute
num
ber
ICO
S+ T
fh ce
lls
P = 0.025P = 0.009
PD-1 Triggering affects TFH function
Cubas RA et al. Nature Med. 2013
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Can these functions be restored?
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P < 0.03
CD27
MFI
(B ce
lls)
CXCR5hi CXCR5- CD45RA+0
10002000300040005000600070008000 CTRL
IL-21 (10ng/ml)
IgG
(ng/
ml)
-IL-21 +IL21 HIV- LN
-IL-21 +IL21
IgG
(ng/
ml)
P < 0.02
P < 0.03
HIV+ LN
HIV+ LN
Exogenous IL-21 enhances TFH function
CD27
MFI
(B ce
lls)
-IL21 +IL21 +IL21 (10ng/ml) (40ng/ml)
P < 0.02
P < 0.02
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Tota
l IgG
(ng/
ml)
Tota
l IgG
(ng/
ml)
-IL-21 +IL21
Isotype αPD-L1/L2
HIV+ LN (Gag-Env stimulation)
HIV+ LN (Gag-Env stimulation)
Enhancing HIV-specific TFH function by interfering with PD-1/IL-21 axis
Cubas RA et al. Nature Med. 2013
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Hypothesis model
Lymph nodeB cell follicle
Germinal center
TFH
Plasma cell
Memory B cell
Germinal center B cell
IL-21
HIV viremia
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Summary I
• HIV-specific TFH cells are expanded in chronic infection
• Expansion of TFH cells correlated with skewing of B cell subsets in chronic HIV infection
• Hypersecretion of IgG1 was associated with BCL6 expression in TFH cells
• TFH serve as a viral reservoir and promote HIV replication
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Summary II
• B memory cell responses are skewed in HIV infection
• PD-L1 is overexpressed on B cells in HIV infection and down regulates TFH function
• TFH and B cell function can be restored by anti-PD-1 and/or
exogenous II-21
• TFH cells may represent the primary obstacle for achieving functional
HIV cure
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Pathogenesis Model
Vinuesa CG, JCI 2012
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O. DegenS. HertlingA. HüfnerS. Schmiedel
J. Schulze zur WieschI. TothP. HartjenS. Kummer
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O. DegenS. HertlingA. HüfnerS. Schmiedel
J. Schulze zur WieschI. TothP. HartjenS. Kummer
Slides and data provided by:C. Petrovas, R. Koup (VRC, NIH, USA)M. Lindqvist, H. Streeck (Ragon Inst., MGH, Boston, USA)M. Perreau, G. Pantaleo (Univ. of Lausanne, Switzerland)R. Cubas, E. Haddad (VGTI, Florida, USA)