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14-J281 Transgenic Nonobese Diabetic Mice Is Associated with a Th2 Shift Circumscribed Regionally to the Islets and Functionally to Islet Autoantigen1
Institut National de la Santé et de la Recherche Médicale, Unité 25, Hôpital Necker, Paris, France
The onset of autoimmune diabetes is related to defective immune
regulation. Recent studies have shown that NK T cells are deficient in
number and function in both diabetic patients and nonobese diabetic
(NOD) mice. NK T cells, which are CD1d restricted, express a TCR with
an invariant V
14-J281 chain and rapidly produce large amounts of
cytokines. V14-J281 transgenic NOD mice have increased numbers of
NK T cells and are protected against diabetes onset. In this study we
analyzed where and how NK T cells interfere with the development of the
anti-islet autoimmune response. NK T cells, which are usually rare
in lymph nodes, are abundant in pancreatic lymph nodes and are also
present in islets. IL-4 mRNA levels are increased and IFN-
mRNA
levels decreased in islets from diabetes-free V14-J281 transgenic
NOD mice; the IgG1/IgG2c ratio of autoantibodies against glutamic acid
decarboxylase is also increased in these mice. Treatment with IL-12 (a
pro-Th1 cytokine) or anti-IL-4 Ab abolishes the diabetes protection
in V14-J281 NOD mice. The protection from diabetes conferred by
NK T cells is thus associated with a Th2 shift within islets directed
against autoantigen such as glutamic acid decarboxylase. Our findings
also demonstrate the key role of IL-4.
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