A divalent human leukocyte antigen-B7 fusion-protein up-regulates CD25 and CD69 in alloreactive CD8+ T cells bypassing CD28 costimulation.
BACKGROUND
T cells recognize major histocompatibility complex (MHC) molecules and their cryptic antigenic peptides on antigen-presenting cells and are generally triggered to proliferate, and when sufficient, co-stimulation is available. In soluble form, monomeric MHC molecules can induce apoptosis, anergy, or decreases of the T-cell receptor (TCR).


METHODS
A dimeric fusion protein of the human leukocyte antigens (HLA)-B7 was molecularly engineered and expressed in a B-cell line to allow secretion. Alloreactive T cells were generated according to the standard protocol.


RESULTS
A dimer of approximately 160 kD was obtained, affinity purified, and used to study T-cell interaction. In immobilized form, this protein efficiently stimulated alloreactive T cells to proliferate and produce interleukin (IL)-2 and interferon (IFN)-gamma in a concentration-dependent manner, up-regulating CD25 and CD69 expression. In contrast, the soluble fusion protein induced T-cell apoptosis.


CONCLUSIONS
The dichotomy in T-cell regulation by a divalent MHC fusion protein warrants the use of MHC multimers as custom-designed immune-regulatory molecules both in transplantation and autoimmune disease.
Rickert
Uta
U
Institute of Anatomy, University of Kiel, Germany.
Welke
Judith
J
Behrens
Dirk
D
Zavazava
Nicholas
N
D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis; D001402:B-Lymphocytes; D018122:B7-1 Antigen / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D019281:Dimerization; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D037181:Lectins, C-Type; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection; D015854:Up-Regulation; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D018819:Dipeptidyl Peptidase 4; D006680:HLA Antigens; D037181:Lectins, C-Type; D011993:Recombinant Fusion Proteins; D000099192:CD69 Antigens