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. 2003 Dec;110(4):519-26.
doi: 10.1111/j.1365-2567.2003.01779.x.

Innate immune response to encephalomyocarditis virus infection mediated by CD1d

Mark A Exley  1 , Nancy J Bigley, Olivia Cheng, Angela Shaulov, Syed Muhammad Ali Tahir, Quincy L Carter, Jorge Garcia, Carren Wang, Kurt Patten, Harold F Stills, Frederick W Alt, Scott B Snapper, Steven P Balk
Affiliations

Innate immune response to encephalomyocarditis virus infection mediated by CD1d

Mark A Exley et al. Immunology. 2003 Dec.

Abstract

CD1d-reactive natural killer T (NKT) cells can rapidly produce T helper type 1 (Th1) and/or Th2 cytokines, can activate antigen-presenting cell (APC) interleukin-12 (IL-12) production, and are implicated in the regulation of adaptive immune responses. The role of the CD1d system was assessed during infection with encephalomyocarditis virus (EMCV-D), a picornavirus that causes acute diabetes, paralysis and myocarditis. EMCV-D resistance depends on IL-12-mediated interferon-gamma (IFN-gamma) production. CD1d-deficient mice, which also lack CD1d-reactive NKT cells, were substantially more sensitive to infection with EMCV-D. Infected CD1d knockout mice had decreased IL-12 levels in vitro and in vivo, and indeed were protected by treatment with exogenous IL-12. IFN-gamma production in CD1d knockout mice was decreased compared with that in wild-type (WT) mice in response to EMCV-D in vitro, although differences were not detected in vivo. Treatment with anti-asialo-GM1 antibody, to deplete NK cells, caused a marked increase in susceptibility of WT mice to EMCV-D infection, whereas CD1d knockout mice were little affected, suggesting that NK-cell-mediated protection is CD1d-dependent. Therefore, these data indicate that CD1d is essential for optimal responses to acute picornaviral infection. We propose that CD1d-reactive T cells respond to early immune signals and function in the innate immune response to a physiological viral infection by rapidly augmenting APC IL-12 production and activating NK cells.

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Figures

Figure 1
Figure 1
Generation of CD1d-deficient mice. (a) Map of murine CD1d.1 and CD1d.2 loci and gene targeting construct. (b) (left panel) Southern blot of ScaI-digested ES cells with the 5′-SacI–HindIII probe. Lane 1, WT with arrow indicating WT band; lane 2, homologous recombinant with 0·5 kb smaller band indicated with arrowhead; (right panel) Southern blot of NheI-digested ES cells with the 3′-BglII probe, lanes 1 and 2 as above. (c) Flow cytometry of (129 × C57BL/6)F2 WT or CD1d KO spleen cells stained with anti-CD1d (bold) or isotype control (ISO) antibodies.
Figure 2
Figure 2
EMCV-D infection of WT and CD1d KO mice. (a) Eight-week-old (129 × C57BL/6)F2 WT and CD1d KO male mice were infected with EMCV-D and assessed for paralysis on days 5 and 6, differences between the WT and CD1d KO were significant (P < 0·01). (b) Eight-week-old (129 × C57BL/6)F2 WT and CD1d KO male mice infected with EMCV-D and analysed by glucose tolerance testing at 7 days post-infection. Hyperglycaemia was defined as values >3 times the SD over the mean value of phosphate-buffered-saline-injected uninfected controls, differences between the WT and CD1d KO were significant (P < 0·03). (c) Six-week-old-male C57BL/6 CD1d KO and WT mice infected with EMCV-D and analysed by glucose tolerance testing, differences between WT and CD1d KO were significant (P < 0·05).
Figure 3
Figure 3
Cytokine production in vivo and in splenocytes cultures. (a) Splenocyte IFN-γ production from replicate cultures following EMCV-D infection in vitro of cells from 8-week-old WT and CD1d KO male (129 × C57BL/6)F2 mice. (b) Splenocyte p70 IL-12 production following EMCV-D infection as in Fig. 2(a). (c) Endogenous serum p70 IL-12 levels prior to and during EMCV-D infection of 8-week-old WT and CD1d KO male (129 × C57BL/6)F2 mice (n > 5). (d) Individual 6-week-old-male C57BL/6 WT and CD1d KO serum p70 IL-12 levels at 6 days after EMCV-D infection.
Figure 4
Figure 4
Effects of exogenous IL-12 on EMCV-D infection of WT and CD1d KO mice. (a) WT and CD1d KO (129 × C57BL/6)F2 mice treated with IL-12 or phosphate-buffered saline (PBS) were infected with EMCV-D and assessed for paralysis at day 7 (n = 6/group). (b) Serum IFN-γ from the experiment shown in (a) determined 7 days post-infection. (c) Splenocyte IFN-γ production on log scale following EMCV-D infection ±IL-12 (1 ng/ml). Uninfected cultures contained no detectable cytokine.
Figure 5
Figure 5
NK cell depletion in EMCV-D-infected CD1d KO and WT mice. WT and CD1d KO (129 × C57BL/6)F2 mice were pretreated with anti-ASGM1 (CD1d KO n = 9; WT n = 6) or IgG control (CD1d KO, n = 8; WT, n = 4) 24 hr prior to EMCV-D infection and glucose tolerance testing was performed on day 7.
Figure 6
Figure 6
Model for surveillance for viral infection by CD1d-reactive NKT cells. Dying virus-infected cells are phagocytosed and digested in CD1d+ phagocytic vacuoles. CD1d presents glycoplipids from the infected cell to local CD1d-reactive NKT cells. CD1d-reactive NKT cell IFN-γ induces APC IL-12 production, amplifying CD1d-reactive NKT cell and APC activation. IL-12 and/or IFN-γ rapidly activate innate NK cells and subsequently contribute to the activation of adaptive cytotoxic T-cell responses downstream.
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