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.
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.
Authors: Sabrina Bonde; Amy M Dowden; Kun-Ming Chan; William B Tabayoyong; Nicholas Zavazava Journal: Transplantation Date: 2008-12-27 Impact factor: 4.939