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Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8603, Université Paris V, Hôpital Necker, Paris, France
The period that precedes onset of insulin-dependent diabetes
mellitus corresponds to an active dynamic state in which pathogenic
autoreactive T cells are kept from destroying ß cells by regulatory T
cells. In prediabetic nonobese diabetic (NOD) mice, CD4+
splenocytes were shown to prevent diabetes transfer in immunodeficient
NOD recipients. We now demonstrate that regulatory splenocytes belong
to the CD4+ CD62Lhigh T cell subset that
comprises a vast majority of naive cells producing low levels of IL-2
and IFN-
and no IL-4 and IL-10 upon in vitro stimulation.
Consistently, the inhibition of diabetes transfer was not mediated by
IL-4 and IL-10. Regulatory cells homed to the pancreas and modified the
migration of diabetogenic to the islets, which resulted in a decreased
insulitis severity. The efficiency of CD62L+ T cells was
dose dependent, independent of sex and disease prevalence. Protection
mechanisms did not involve the CD62L molecule, an observation that may
relate to the fact that CD4+ CD62Lhigh lymph
node cells were less potent than their splenic counterparts. Regulatory
T cells were detectable after weaning and persist until disease onset,
sustaining the notion that diabetes is a late and abrupt event. Thus,
the CD62L molecule appears as a unique marker that can discriminate
diabetogenic (previously shown to be CD62L-) from
regulatory T cells. The phenotypic and functional characteristics of
protective CD4+ CD62L+ cells suggest they are
different from Th2-, Tr1-, and NK T-type cells, reported to be
implicated in the control of diabetes in NOD mice, and may represent a
new immunoregulatory population.
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A. M. Yamamoto, Y. Chernajovsky, F. Lepault, O. Podhajcer, M. Feldmann, J.-F. Bach, and L. Chatenoud The Activity of Immunoregulatory T Cells Mediating Active Tolerance Is Potentiated in Nonobese Diabetic Mice by an IL-4-Based Retroviral Gene Therapy J. Immunol., April 15, 2001; 166(8): 4973 - 4980. [Abstract] [Full Text] [PDF]
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J. Salaun, N. Simmenauer, P. Belo, A. Coutinho, and N. M. Le Douarin Grafts of supplementary thymuses injected with allogeneic pancreatic islets protect nonobese diabetic mice against diabetes PNAS, January 22, 2002; 99(2): 874 - 877. [Abstract] [Full Text] [PDF]
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K. Jooss, B. Gjata, O. Danos, H. von Boehmer, and A. Sarukhan Regulatory function of in vivo anergized CD4+ T cells PNAS, July 17, 2001; 98(15): 8738 - 8743. [Abstract] [Full Text] [PDF]
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