Exacerbated Susceptibility to Infection-Stimulated Immunopathology in CD1d-Deficient Mice

Abstract

Mice lacking functional CD1d genes were used to study mechanisms of resistance to the protozoan parasite Toxoplasma gondii. Wild-type (WT) BALB/c mice, CD1d-deficient BALB/c mice, and WT C57BL/6 mice all survived an acute oral infection with a low dose of mildly virulent strain ME49 T. gondii cysts. In contrast, most CD1d-deficient C57BL/6 mice died within 2 wk of infection. Despite having parasite burdens that were only slightly higher than WT mice, CD1d-deficient C57BL/6 mice displayed greater weight loss and intestinal pathology. In C57BL/6 mice, CD4+ cells can cause intestinal pathology during T. gondii infection. Compared with WT mice, infected CD1d-deficient C57BL/6 mice had higher frequencies and numbers of activated (CD44high) CD4+ cells in mesenteric lymph nodes. Depletion of CD4+ cells from CD1d-deficient mice reduced weight loss and prolonged survival, demonstrating a functional role for CD4+ cells in their increased susceptibility to T. gondii infection. CD1d-deficient mice are deficient in Vα14+ T cells, a major population of NKT cells. Involvement of these cells in resistance to T. gondii was investigated using gene-targeted Jα18-deficient C57BL/6 mice, which are deficient in Vα14+ T cells. These mice did not succumb to acute infection, but experienced greater weight loss and more deaths than B6 mice during chronic infection, indicating that Vα14+ cells contribute to resistance to T. gondii. The data identify CD4+ cells as a significant component of the marked susceptibility to T. gondii infection observed in CD1d-deficient C57BL/6mice, and establish T. gondii as a valuable tool for deciphering CD1d-dependent protective mechanisms.

Invariant and Noninvariant Natural Killer T Cells Exert Opposite Regulatory Functions on the Immune Response during Murine Schistosomiasis

“…Compared to WT mice, CD1d Ϫ/Ϫ mice developed a markedly reduced Th2 response but maintained their ability to promote a Th1 response. This result is important since it not only confirms our previous observations of BALB/c mice (19) but also suggests that, unlike in other infection models (28,50), differences in the genetic background of the host (C57BL/6 versus BALB/c) do not appear to influence the regulatory impact of NKT-cell functions on the global immune response in our model. On the other hand, C57BL/6 TCR J␣18 Ϫ/Ϫ mice mounted a dramatically decreased Th1 cytokine response, relative to WT mice.…”

A Key Role for Itk in Both IFNγ and IL-4 Production by NKT Cells

“…The original description of immune defects in the absence of Itk demonstrated increased susceptibility of itk Ϫ/Ϫ mice to Toxoplasma gondii infection despite similar frequencies of IFN-␥-producing immune cells on in vitro restimulation with soluble tachyzoite Ag 30 days after infection (59). The generation of antimicrobial effectors but subsequent death from T. gondii infection may also be explained by a defect in NKT cell function given a number of reports suggest a protective role for NKT cells in limiting T. gondii-induced immune pathology (60,61).…”

Interleukin 23 in IBD Pathogenesis

“…Some studies documented a reduction in type I iNKT cells in the blood and intestinal tissue of CD and UC patients [156] (see the review for detailed role of iNKT in IBD [155]). Because iNKT cells produce IL-4, IL-13 and can promote Th2-responses, they have been experimentally shown to play a protective role in various murine IBD models including DSS [157,158], TNBS [159], naïve CD4 + T-cell transfer [160] and T. gondii induced [161,162] models of colitis. However, exactly how IL-23-dependent production of IL-22 or IL-17 by iNKT cells confers protection or impacts IBD pathogenesis has not been fully elucidated.…”