PLA2G1B is involved in CD4 anergy and CD4 lymphopenia in HIV-infected patients
Julien Pothlichet, … , Gérard Lambeau, Jacques Thèze
Julien Pothlichet, … , Gérard Lambeau, Jacques Thèze
Published March 3, 2020
Citation Information: J Clin Invest. 2020;130(6):2872-2887. https://doi.org/10.1172/JCI131842.
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Research Article AIDS/HIV Immunology Article has an altmetric score of 47

PLA2G1B is involved in CD4 anergy and CD4 lymphopenia in HIV-infected patients

Abstract

The precise mechanism leading to profound immunodeficiency of HIV-infected patients is still only partially understood. Here, we show that more than 80% of CD4+ T cells from HIV-infected patients have morphological abnormalities. Their membranes exhibited numerous large abnormal membrane microdomains (aMMDs), which trap and inactivate physiological receptors, such as that for IL-7. In patient plasma, we identified phospholipase A2 group IB (PLA2G1B) as the key molecule responsible for the formation of aMMDs. At physiological concentrations, PLA2G1B synergized with the HIV gp41 envelope protein, which appears to be a driver that targets PLA2G1B to the CD4+ T cell surface. The PLA2G1B/gp41 pair induced CD4+ T cell unresponsiveness (anergy). At high concentrations in vitro, PLA2G1B acted alone, independently of gp41, and inhibited the IL-2, IL-4, and IL-7 responses, as well as TCR-mediated activation and proliferation, of CD4+ T cells. PLA2G1B also decreased CD4+ T cell survival in vitro, likely playing a role in CD4 lymphopenia in conjunction with its induced IL-7 receptor defects. The effects on CD4+ T cell anergy could be blocked by a PLA2G1B-specific neutralizing mAb in vitro and in vivo. The PLA2G1B/gp41 pair constitutes what we believe is a new mechanism of immune dysfunction and a compelling target for boosting immune responses in HIV-infected patients.

Authors

Julien Pothlichet, Thierry Rose, Florence Bugault, Louise Jeammet, Annalisa Meola, Ahmed Haouz, Frederick Saul, David Geny, José Alcami, Ezequiel Ruiz-Mateos, Luc Teyton, Gérard Lambeau, Jacques Thèze

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Figure 7

Immunological effects of hPLA2G1B on mouse CD4+ T cells in vitro and in vivo.

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Immunological effects of hPLA2G1B on mouse CD4+ T cells in vitro and in ...
(A–G) FACS analysis of the effect of hPLA2G1B on mouse CD4+ T cells after anti-CD3/CD28 and IL-2 stimulation (5 days, see gating strategy on Supplemental Figure 6C). (A–E) mCD4+ T cells were pretreated with WT or H48Q hPLA2G1B. (A) CD25 expression after treatment with 125 nM hPLA2G1B. (B) CD25 expression (MFI) and (C) cell survival (n = 3, 10 mice). (D) mCD4+ T cell proliferation profile after treatment with 125 nM hPLA2G1B. (E) Percentage of live mCD4+ T cells per cell generation (Go to G5; n = 3, 9 mice). (F and G) Effects of mAb anti-PLA2G1B 14G9 in vitro treatment on 125 nM hPLA2G1B action on CD4+ T cell survival and CD25 expression (n = 4, 11 mice). (H–L) In vivo effects of hPLA2G1B on CD4+ T cell response to IL-7. Spleen CD4+ T cells were isolated after intraperitoneal injection into C57BL/6 mice and the ex vivo p-STAT5 NT response to IL-7 was evaluated by confocal microscopy, with an average of 200 cells examined for each condition. Effect of hPLA2G1B injection at several doses of PLA2G1B for 3 hours (H, 6 mice, 2 experiments) and at several times after injection (I, 3 mice, 1 experiment; J, 8 mice, 2 experiments). (K) Effects of mAb anti-hPLA2G1B 14G9 injected in vivo on the hPLA2G1B (100 μg, 3 hours) response (5 mice, 1 experiment). (L) Inhibition of the effects of hPLA2G1B after injection into hPLA2G1B/BSA–immunized mice (5 mice, 1 experiment). Results are shown as the mean ± SEM (B, C, and E–G) or mean ± SD (H–L). *P < 0.05; **P < 0.01; ***P < 0.001 adjusted for multiple comparisons by Kruskal-Wallis test P < 0.001, followed by the Mann-Whitney test (B) and 2-way ANOVA with correction for multiple comparisons by Tukey’s (C, H, and J–L), Dunnett’s for the condition without PLA2G1B as a control group (E), or Sidak’s (F, G, and I) post hoc test.