Expression of preproinsulin-2 gene shapes the immune response to preproinsulin in normal mice.
Deciphering mechanisms involved in failure of self tolerance to preproinsulin-2 is a key issue in type 1 diabetes. We used nonautoimmune 129SV/Pas mice lacking preproinsulin-2 to study the immune response to preproinsulin-2. In these mice, a T cell response was detected after immunization with several preproinsulin-2 peptides and confirmed by generating hybridomas. Activation of some of these hybridomas by wild-type (wt) islet cells or recombinant murine proinsulin-2 demonstrated that two epitopes can be generated from the naturally expressed protein. Although T cells from wt mice responded to preproinsulin-2 peptides, we could not detect a response to the naturally processed epitopes in these mice. Moreover, after immunization with recombinant whole proinsulin-2, a T cell response was detected in preproinsulin-2-deficient but not in wt mice. This suggests that islet preproinsulin-2-autoreactive T cells are functionally eliminated in wt mice. We used a transplantation model to evaluate the relevance of reactivity to preproinsulin-2 in vivo. Wild-type preproinsulin-2-expressing islets transplanted in preproinsulin-2-deficient mice elicited a mononuclear cell infiltration and insulin Abs. Graft infiltration was further increased by immunization with preproinsulin-2 peptides. Preproinsulin-2 expression thus shapes the immune response and prevents self reactivity to the islet. Moreover, islet preproinsulin-2 primes an immune response to preproinsulin-2 in deficient mice.
Faideau
Béatrice
B
Institut National de la Santé et de la Recherche Médicale, Unité 561, Groupe Hospitalier Cochin-Saint Vincent de Paul, 82 avenue Denfert Rochereau, 75014 Paris, France.
Briand
Jean-Paul
JP
Lotton
Chantal
C
Tardivel
Isabelle
I
Halbout
Philippe
P
Jami
Jacques
J
Elliott
John F
JF
Krief
Patricia
P
Muller
Sylviane
S
Boitard
Christian
C
Carel
Jean-Claude
JC
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology*; D006825:Hybridomas; D007328:Insulin; D007376:Interleukin-2 / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D011384:Proinsulin / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics* / Q000276:immunology*; D020033:Protein Isoforms / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D011498:Protein Precursors / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics* / Q000276:immunology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D023001:Transplantation Tolerance / Q000235:genetics; D014611:Vaccination
D007328:Insulin; D007376:Interleukin-2; D010446:Peptide Fragments; D020033:Protein Isoforms; D011498:Protein Precursors; D011994:Recombinant Proteins; C013737:preproinsulin; D011384:Proinsulin