DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype.
Recently, we have identified proinsulin (P-Ins)(73-90) as an immunodominant T cell epitope of HLA-DRB1*0401 (DR4) subjects with beta-islet cell autoimmunity and of HLA-DR4/CD4 double-transgenic mice immunized with human P-Ins. We have compared the fine specificities of one human CD4 T cell clone and two mouse T cell hybridoma clones recognizing this epitope, and, although these three clones all recognized the same core region (LALEGSLQK), there were major differences in how they interacted with the peptide (p)/HLA complex, reflecting the fact that human P-Ins is a foreign antigen in the mouse and an autoantigen in the type 1 diabetes patient. The human T cell clone was forkhead transcription factor 3 (Foxp3)-positive, a marker for regulatory T cell lineages, and secreted predominantly IL-5, IL-10, and low levels of IFNgamma in response to P-Ins(73-90). This finding is compatible with the previously detected regulatory cytokine pattern in subjects with beta-cell autoimmunity. However, added N- or C-terminal amino acids drastically changed HLA and tetramer binding capacity as well as T cell reactivity and the cytokine phenotype of the P-Ins(73-90)-specific human CD4 T cell clone, suggesting a potential for this P-Ins epitope as a target for therapeutic intervention in HLA-DR4-positive humans with beta-islet cell autoimmunity or recent-onset type 1 diabetes.
Durinovic-Belló
Ivana
I
Department of Internal Medicine I, Division of Endocrinology, University of Ulm, D-89081 Ulm, Germany.
Rosinger
Silke
S
Olson
Jennifer A
JA
Congia
Mauro
M
Ahmad
Regina C
RC
Rickert
Mathias
M
Hampl
Johannes
J
Kalbacher
Hubert
H
Drijfhout
Jan W
JW
Mellins
Elizabeth D
ED
Al Dahouk
Sascha
S
Kamradt
Thomas
T
Maeurer
Markus J
MJ
Nhan
Carol
C
Roep
Bart O
BO
Boehm
Bernhard O
BO
Polychronakos
Constantin
C
Nepom
Gerald T
GT
Karges
Wolfram
W
McDevitt
Hugh O
HO
Sønderstrup
Grete
G
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000939:Epitopes; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006684:HLA-DR Antigens / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D010641:Phenotype; D011384:Proinsulin / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000596:Amino Acids; D000939:Epitopes; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D010446:Peptide Fragments; D011384:Proinsulin