The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/2000/1/213/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 2, January 17, 2000 213-224

Original Article

A Single Amino Acid Determines the Immunostimulatory Activity of Interleukin 10

Yaozhong Dinga,b, Lihui Qinb, Serguei V. Kotenkoc, Sidney Pestkac, and Jonathan S. Bromberga,b

a Department of Microbiology and Immunology, The University of Michigan Medical Center, Ann Arbor, Michigan 48109
b Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York 10029-6574
c Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635
Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1496, New York, NY 10029-6574.212-849-2437212-241-8938

jon_bromberg{at}smtplink.mssm.edu

Cellular interleukin 10s (cIL-10s) of human and murine origin have extensive sequence and structural homology to the Epstein-Barr virus BCRF-I gene product, known as viral IL-10 (vIL-10). Although these cytokines share many immunosuppressive properties, vIL-10 lacks several of the immunostimulatory activities of cIL-10 on certain cell types. The molecular and cellular bases for this dichotomy are not currently defined. Here, we show that the single amino acid isoleucine at position 87 of cIL-10 is required for its immunostimulatory function. Substitution of isoleucine in cIL-10 with alanine, which corresponds to the vIL-10 residue, abrogates immunostimulatory activity for thymocytes, mast cells, and alloantigenic responses while preserving immunosuppressive activity for inhibition of interferon {gamma} production and prolongation of cardiac allograft survival. Conversely, substitution of alanine with isoleucine in vIL-10 converts it to a cIL-10–like molecule with immunostimulatory activity. This single conservative residue alteration significantly affects ligand affinity for receptor; however, affinity changes do not necessarily alter specific activities for biologic responses in a predictable fashion. These results suggest complex regulation of IL-10 receptor–ligand interactions and subsequent biological responses. These results demonstrate that vIL-10 may represent a captured and selectively mutated cIL-10 gene that benefits viral pathogenesis by leading to ineffective host immune responses. The ability to manipulate the activity of IL-10 in either a stimulatory or suppressive direction may be of practical value for regulating immune responses for disease therapy, and of theoretical value for determining what aspects of IL-10 activity are important for normal T cell responses.

Key Words: interleukin 10 • stimulation • suppression • affinity • signaling

Abbreviations used in this paper: CHO, Chinese hamster ovary; cIL-10, cellular IL-10; EMSA, electrophoretic mobility shift assay; h, human; hIL-10(I87A), the isoleucine to alanine substitution at position 87 of hIL-10; JAK, Janus kinase; m, mouse; STAT, signal transducer and activator of transcription; vIL-10, viral IL-10; vIL-10(A87I), the alanine to isoleucine substitution at position 87 of vIL-10.

© 2000 The Rockefeller University Press


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