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Abstract
BACKGROUND & AIMS: V alpha14 invariant natural killer T cells (iNKT) are localized in peripheral tissues such as the liver rather than lymphoid tissues. Therefore, their role in modulating the stimulation of conventional, major histocompatibility complex (MHC)-restricted T-cell responses has remained ambiguous. We here describe a role for V alpha14 iNKT cells in modulating conventional T-cell responses to antigen expressed in liver, using transferrin-mOVA (Tf-mOVA) mice. METHODS: Naïve ovalbumin-specific class I MHC-restricted T cells (OTI) were adoptively transferred into Tf-mOVA mice in the presence or absence of iNKT-cell agonist alpha-galactosylceramide, after which OTI T-cell priming, antigen-specific cytokine production, cytotoxic killing ability, and liver damage were analyzed. RESULTS: Transfer of OTI cells resulted in robust intrahepatic, antigen-specific proliferation of T cells. OTI T cells were activated in liver, and antigen-specific effector function was stimulated by coactivation of Valpha14 iNKT cells using alpha-galactosylceramide. This stimulation was absent in CD1d(-/-)Tf-mOVA mice, which lack V alpha14 iNKT cells, and was prevented when interferon-gamma and tumor necrosis factor-alpha production by V alpha14 iNKT cells was blocked. CONCLUSIONS: CD1d-restricted V alpha14 iNKT cells stimulate intrahepatic CD8 T-cell effector responses to antigen expressed in liver. Our findings elucidate a previously unknown intervention point for targeted immunotherapy to autoimmune and possibly infectious liver diseases.
Original language | English |
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Pages (from-to) | 2132-2143 |
Number of pages | 12 |
Journal | Gastroenterology |
Volume | 134 |
DOIs | |
Publication status | Published - 1 Jan 2008 |
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Modulation of Immune Responses by aGalCer Analogues Through Differential Activation of CD1d-restricted NKT Cells
Besra, D. & Lammas, T.
1/06/05 → 30/11/09
Project: Research Councils