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Gene Complementation in the T Lymphocyte Proliferative Response to Poly (Glu⁵⁷Lys³⁸Tyr⁵): Evidence for Effects of Polymer Handling and Gene Dosage¹

From the Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20014 and the Department of Biochemistry, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Abstract

This paper explores the difficulties encountered in demonstrating Ir gene complementation in the immune response to the synthetic terpolymer, poly(Glu⁵⁷-Lys³⁸Tyr⁵) [GLT⁵]. First, the method by which the polymer was put into solution influenced the outcome because some determinants on GLT⁵ were found to be sensitive to exposure to alkaline conditions. Second, the dose of antigen used for immunization was shown to be critical since mice of the H-2^q haplotype failed to respond to low doses of GLT⁵. Third, prolonged storage of dialyzed and lyophilized GLT⁵ led to alterations in the solubility properties of the polymer with consequent loss of some of the antigenic determinants. Finally, differences in the genetic make up of the responding strains affected the overall response. Each responder haplotype recognized different determinants on the polymer, or the same determinant in different ways, such that variations in polymer handling appeared to influence selectively the immunogenicity and antigenicity of GLT⁵ for each strain. Furthermore, the critical (B10 x B10.A)F₁ strain, whose response was required to demonstrate conclusively complementation, failed to respond well to certain altered preparations of the polymer in which the determinants being recognized were present in low concentration. This failure, in contrast to the high responsiveness of the genetically similar B10.A(5R) strain, was shown by the low response of [B10.A(4R) x B10.A(5R)] F₁ mice to result from a gene dosage effect. However, under optimal conditions of antigen handling, (B10 x B10.A)F₁ mice did respond well to GLT⁵, demonstrating that two complementing MHC-linked Ir genes are involved in the recognition of certain determinants on this polymer.

Footnotes

¹ This work was supported in part by the following grants: National Institute of Allergy and Infectious Diseases, A107825; American Cancer Society Grant, IM-5F; and National Foundation-March of Dimes, I-492.

² Address reprint requests to: Dr. Ronald H. Schwartz, Bldg. 10, Room 11N310, Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20205.