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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 Article has an altmetric score of 56

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

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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 2

Type I NKT and NKT-like cells are recruited to DENV-infected skin and dLNs.

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Type I NKT and NKT-like cells are recruited to DENV-infected skin and dL...
(A) Various NKT cell subsets from the skin and dLNs were identified by flow cytometry using CD1d tetramer staining and additional markers, including iNKT (NK1.1+CD3+CD1d-tetramer+), type II NKT cells (NK1.1+CD3+CD1d-tetramer–CD4+, which have a phenotype similar to that of NK1.1+CD4+ T cells), NKT-like NKT cells (NK1.1+CD3+CD1d-tetramer–CD8+), and CD1d-tetramer– CD4 CD8 DN NKT cells (NK1.1+CD3+CD1d-tetramer–CD4–CD8–). FSC, forward scatter; SSC, side scatter. (B) The unbiased clustering tSNE algorithm was used to verify flow cytometry data in the FP skin and dLNs. The algorithm was run on concatenated total samples (infected and uninfected). iNKT cells were absent in CD1d-KO mice. (C) Total NKT cells were quantified in the skin in WT and CD1d-KO mice after infection with 2 × 105 PFU of DENV2 s.c. by FP injection. DENV infection increased iNKT cells in WT but not in CD1d-KO mice in the (D) skin and (E) dLNs on days 3 and 5 after infection. (F) Quantification of CD1dind NKT cell subsets in the FP showed increased NKT-like cells at days 3 and 5 after infection in WT but not CD1d-KO mice, while other NKT cell subsets measured were not influenced. (G) Tracking of local versus recruited NKT-like cells in the skin, performed by CFSE labeling prior to DENV2 infection. CFSE+ or CFSE– NKT-like cell (NK1.1+CD3+CD1d-tetramer–CD8+) numbers in the FP skin were determined on day 3 after infection and are presented as stacked bars. iNKT and NKT-like cells were recruited into the skin during DENV infection, and both subsets were absent from the skin of CD1d-KO mice. Data are represented as means ± SEM and are for n = 5 mice combined from 2 independent experiments for each time point. *P < 0.05; **P < 0.01; ***P < 0.001, 1- or 2-way ANOVA with Holm-Šidák post test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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