alpha4 integrins and L-selectin differently orchestrate T-cell activity during diabetes prevention following oral administration of CTB-insulin.
Oral administration of insulin conjugated to the B chain of cholera toxin (CTB-insulin) in non-obese diabetic (NOD) mice results in diabetes prevention. We investigated the respective contributions of L-selectin (CD62L) and alpha4-integrin pathways during CTB-driven tolerance. Purified CD62L+CD4+ cells from CTB-insulin fed mice significantly reduced the capacity of diabetogenic T cells to transfer diabetes in syngeneic recipients. In vivo antibody blockade of fed animals during adoptive co-transfer experiments indicated that both CD62L and alpha4-integrins pathways were necessary to develop a protective response after oral tolerance induction. In contrast, when antibodies were given to recipient mice, only CD62L was critical for the protection. In vitro stimulated CD62L+CD4+ cells from the spleen of fed animals secreted lower amounts of IL-4 and IL-10 but comparable levels of TGFbeta than CD62L-cells. A reduced IFN-gamma production between the two cell subsets was specifically observed in CTB-insulin fed mice. Furthermore, antibody treatments induced changes in T-cell migration to the spleen, mesenteric and pancreatic lymph nodes. The protective effect was also associated with migration of regulatory T cells into pancreatic islets. Taken together, our results suggest that L-selectin and alpha4-integrin have distinct but complementary roles in the generation and function of regulatory CD4+ T cells following CTB-insulin administration.
Aspord
Caroline
C
INSERM 449, Faculté de Médecine Laennec, Lyon, France.
Czerkinsky
Cecil
C
Durand
Annie
A
Stefanutti
Anne
A
Thivolet
Charles
C
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002772:Cholera Toxin / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D039441:Integrin alpha4 / Q000378:metabolism*; D019041:L-Selectin / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D013601:T-Lymphocytes / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D015815:Cell Adhesion Molecules; D007004:Hypoglycemic Agents; D007328:Insulin; D019041:L-Selectin; D039441:Integrin alpha4; D002772:Cholera Toxin