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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.

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Presentation on theme: "T follicular helper cells in HIV infection Jan van Lunzen University Medical Center Hamburg-Eppendorf Heinrich-Pette-Institut for Experimental Virology."— Presentation transcript:

1 T follicular helper cells in HIV infection Jan van Lunzen University Medical Center Hamburg-Eppendorf Heinrich-Pette-Institut for Experimental Virology & Immunology Hamburg, Germany

2 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 T FH cells a viral reservoir?  What are the consequences of dysregulated T FH function?  Can these functions be restored?

3 Where does HIV replicate in lymph nodes?

4 Lymph Node Pathology HIV - HIV + Stellbrink & van Lunzen, Curr Opin Infect Dis 2001

5 Immunopathology of LN Tenner-Racz K, Stellbrink HJ, van Lunzen J et al., J Exp Med 1998 CD4+Ki-67+ CD8+

6 Which cells are preferentially infected?

7 Infection rate of CD57+ and CD57- CD4+ T cells in PB and LN10 7,5 5 2, Patient no. Infected cells (%) LN CD57 + CD4 + T cells LN CD57 – CD4 + T cells PBL CD57 + CD4 + T cells PBL CD57 – CD4 + T cells Ratio of the viral loads: CD57+CD4+ T cells [%]/CD57 – CD4+ T cells [%] LN: PBL:0.32.2< Hufert F, van Lunzen J et al.: AIDS 1997

8 What effect/limitations does HAART have?

9 HIV-1 RNA in LN during HAART Tenner-Racz K, Stellbrink HJ, van Lunzen J et al., J Exp Med 1998 van Lunzen J, Ruiz L et al., AIDS 1998 Day 0 Day 28 HIV-1 RNA p24 Ag

10 T cell proliferation in LN during HAART 15%10%5%0 CD4 + Ki-67 + CD8 + Ki-67 + p < 0,0001 pre-treatment (n = 30) post-treatment (n = 30) normal controls (n = 4) van Lunzen J, et al., CROI 1999

11 What is the role of T follicular helper cells in HIV infection?

12 CD4 T FH cells B cell MHC II TCR IL-21 IFNγ IL-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 cell CD40L CD40 CD4 T FH cells are critical for effective antibody responses Bcl6 CXCR5 ICOS ICOSL Bcl6 PD-1

13 SIV: Relative Accumulation of T FH in LN SIV acute SIV chronic (high % of T FH ) SIV - SIV chronic (low % of T FH ) % of CM CD4 T cells p= p< PD-1 CCR ICOS CD150 Petrovas C. et al. JCI 2012

14 PD-1 CCR7 Immune activation rather than direct infection with SIV is associated with in vivo T FH accumulation Chronic SIV (>2 months) SIV Gag DNA (copies/cell) ICOS CD150 p= p= p= sCD14 (x10 6 pg/ml) SIV acute SIV chronic (high % of T FH ) SIV - SIV chronic (low % of T FH ) Petrovas C. et al. JCI 2012

15 Accumulation of T FH is Associated with Increased Frequency of GC-B cells and titers of SIV-specific Antibodies PNA high IgG low PNA high IgG high SIV - SIV + low % T FH SIV + high % T FH p= SIV-specific IgG (titer, x10 4 ) p=0.051 p=0.033 p=0.048 ND SIV acute SIV chronic (low % T FH ) SIV chronic (high % T FH ) gp120gp130gp140p27p55 Petrovas C. et al. JCI 2012

16 High frequency of CXCR5+PD-1 high CD4 T cell subset in the lymph node Lindqvist M et al., JCI 2012

17 IL-21 preferentially produced by T FH cells Lindqvist M et al., JCI 2012

18 Expansion of T FH cells correlated with skewing of B cell subsets GC B cellsLate memory B cellsPlasma B cells Lindqvist M et al., JCI 2012

19 Hypersecretion of IgG was associated with BCL6 expression in T FH cells Lindqvist M et al., JCI 2012

20 Are T FH cells a viral reservoir?

21 T FH 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-CD28 Brefeldin A Perreau M et al JEM 2012

22 T FH Cells and CXCR5 - PD-1 + CD4 T-Cells Are Enriched in CD4 T-Cells Containing HIV DNA DNA extractionTaqman RT-PCR HIV-1 gag gene Perreau M et al JEM 2012

23 T FH 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

24 HIV Isolation from Patients with Low (<1000 HIV RNA copies/mL of plasma) in Different CD4 T-Cell Populations  T FH 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 detection Coated CD3/28 CD8-depleted PBMCs + D7D0 Collection of SNs D3

25 What are the consequences of dysregulated T FH function?

26

27 PD-L1 expression in GC B cells Cubas RA et al. Nature Med. 2013

28 PD-1 ligand and T FH proliferation, activation and cytokine secretion PD1-L Cubas RA et al. Nature Med. 2013

29 IL-21 pg/ml ICOS MFI P = 0.03 P = 0.01 Absolute number ICOS+ Tfh cells P = P = PD-1 Triggering affects T FH function Cubas RA et al. Nature Med. 2013

30 Can these functions be restored?

31 P < 0.03 CD27 MFI (B cells) IgG (ng/ml ) -IL-21 +IL21 HIV- LN -IL-21 +IL21 IgG (ng/ml) P < 0.02 P < 0.03 HIV+ LN Exogenous IL-21 enhances T FH function CD27 MFI (B cells) -IL21 +IL21 +IL21 (10ng/ml) (40ng/ml) P < 0.02

32 Total IgG (ng/ml) -IL-21 +IL21 Isotype αPD-L1/L2 HIV+ LN (Gag-Env stimulation) HIV+ LN (Gag-Env stimulation) Enhancing HIV-specific T FH function by interfering with PD-1/IL-21 axis Cubas RA et al. Nature Med. 2013

33 Hypothesis model Lymph node B cell follicle Germinal center TFH Plasma cell Memory B cell Germinal center B cell IL-21 HIV viremia

34 Summary I HIV-specific T FH cells are expanded in chronic infection Expansion of T FH cells correlated with skewing of B cell subsets in chronic HIV infection Hypersecretion of IgG1 was associated with BCL6 expression in T FH cells T FH serve as a viral reservoir and promote HIV replication

35 Summary II B memory cell responses are skewed in HIV infection PD-L1 is overexpressed on B cells in HIV infection and down regulates T FH function T FH and B cell function can be restored by anti-PD-1 and/or exogenous II-21 T FH cells may represent the primary obstacle for achieving functional HIV cure

36 Pathogenesis Model Vinuesa CG, JCI 2012

37 O. Degen S. Hertling A. Hüfner S. Schmiedel J. Schulze zur Wiesch I. Toth P. Hartjen S. Kummer

38 O. Degen S. Hertling A. Hüfner S. Schmiedel J. Schulze zur Wiesch I. Toth P. Hartjen S. 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)


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