NKT cells promote Th1 immune bias to dengue virus that governs long-term protective antibody dynamics
Youngjoo Choi, … , Abhay P.S. Rathore, Ashley L. St. John
Youngjoo Choi, … , Abhay P.S. Rathore, Ashley L. St. John
Published August 1, 2024
Citation Information: J Clin Invest. 2024;134(18):e169251. https://doi.org/10.1172/JCI169251.
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Research Article Immunology Infectious disease

NKT cells promote Th1 immune bias to dengue virus that governs long-term protective antibody dynamics

Abstract

NKT cells are innate-like T cells, recruited to the skin during viral infection, yet their contributions to long-term immune memory to viruses are unclear. We identified granzyme K, a product made by cytotoxic cells including NKT cells, as linked to induction of Th1-associated antibodies during primary dengue virus (DENV) infection in humans. We examined the role of NKT cells in vivo using DENV-infected mice lacking CD1d-dependent (CD1ddep) NKT cells. In CD1d-KO mice, Th1-polarized immunity and infection resolution were impaired, which was dependent on intrinsic NKT cell production of IFN-γ, since it was restored by adoptive transfer of WT but not IFN-γ–KO NKT cells. Furthermore, NKT cell deficiency triggered immune bias, resulting in higher levels of Th2-associated IgG1 than Th1-associated IgG2a, which failed to protect against a homologous DENV rechallenge and promoted antibody-dependent enhanced disease during secondary heterologous infections. Similarly, Th2 immunity, typified by a higher IgG4/IgG3 ratio, was associated with worsened human disease severity during secondary infections. Thus, CD1ddep NKT cells establish Th1 polarity during the early innate response to DENV, which promotes infection resolution, memory formation, and long-term protection from secondary homologous and heterologous infections in mice, with consistent associations observed in humans. These observations illustrate how early innate immune responses during primary infections can influence secondary infection outcomes.

Authors

Youngjoo Choi, Wilfried A.A. Saron, Aled O’Neill, Manouri Senanayake, Annelies Wilder-Smith, Abhay P.S. Rathore, Ashley L. St. John

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Figure 8

CD1ddep NKT cells promote Th1-associated humoral immunity that protects during homologous and heterologous reinfections.

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CD1ddep NKT cells promote Th1-associated humoral immunity that protects ...
Comparison of serum (A) IgG2a and (B) IgG1 titers between WT and CD1d-KO mice, 3 weeks following DENV2 infection, determined by ELISA. WT and CD1d-KO mice received 1 × 106 PFU of DENV2 via i.p. injection. Endpoint titers were compared by Student’s unpaired t test. *P < 0.05; ***P < 0.001. (C and D) Plaque reduction neutralization test was performed using multiple equivalent concentrations of IgG purified from the serum of WT and CD1d-KO mice. Representative images are shown in D. (E) Schematic diagram of IgG purification from DENV2-immune WT or CD1d-KO mice, followed by immune complex formation with either DENV1 or DENV2 and injection into recipient IFN-αR/IFN-γR-KO mice. (F) Mice were infected with 1 × 105 PFU of DENV2 or immune complexes formed from 1 × 105 PFU of DENV2 and 1 μg of IgG purified from DENV2 postimmune serum from either WT or CD1d-KO mice (homologous challenge). (G) Mice were infected with 2 × 105 PFU of DENV1 or immune complexes formed from 2 × 105 PFU of DENV1 and 10 μg of purified IgG from DENV2 postimmune serum from either WT or CD1d-KO (heterologous challenge). For F and G, DENV virus burden was detected by PCR 5 days after infection. Data are represented as means ± SEM. *P < 0.05; ***P < 0.001, 1-way ANOVA with Holm-Šidák post test. (H) Weight loss was significantly more severe in IFN-αR/IFN-γR–KO mouse transferred antibodies from CD1d-KO DENV2-immune mice compared with those transferred antibodies from WT DENV2-immune mice following DENV1 challenge. Because of missing data resulting from lack of survival, curves were compared by restricted maximum likelihood (REML) mixed effects model and P < 0.0001. (I) Survival also differed significantly in IFN-αR/IFN-γR–KO mice by log-rank test. For A–C and G–I, n = 5 per group. For H, n = 4–5 per group.