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Quantitating Effector and Regulatory T Lymphocytes in Immune Responses by Limiting Dilution Analysis Modeling ¹

Thierry Bonnefoix^*, Philippe Bonnefoix^*, Pascal Perron^*, Jian-Qing Mi^*, Wan Fai Ng, Robert Lechler, Jean-Claude Bensa^*,, Jean-Yves Cahn^* and Dominique Leroux^*

^* Institut National de la Santé de la Recherche Médicale U353, Institut Albert Bonniot, Université Joseph-Fourier, CHRU Grenoble, Fédération d’Onco-Hématologie, Hopital Michallon, Grenoble, France; Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom; and Departement d’Immunologie Cellulaire, Etablissement Français du Sang Rhône-Alpes, Grenoble, France

Although there is currently no doubt that regulatory lymphocytes represent a master player in the immune system, a major unresolved problem is the accurate quantitation of these cells among unfractionated cell populations. This difficulty mainly arises because there are no specific immunophenotypic markers that can reliably discriminate between effector and regulatory lymphocytes. To face this problem, we have developed computational models of limiting dilution analyses addressing the question of the accurate estimation of the frequencies of effector and regulatory cells functionally engaged in an immune response. A set of generic equations were provided to form a framework for modeling limiting dilution data, enabling discrimination between qualitatively different models of suppression. These models include either one or two subpopulations of regulatory cells, featured by either low or potent regulatory activity. The potential of this modeling approach was illustrated by the accurate determination of the frequencies of effector and regulatory T lymphocytes in one real limiting dilution experiment of CD4⁺CD25⁺ T lymphocytes performed in the context of an allogeneic response in the human system. The crucial advantage of the limiting dilution method over the "static, phenotype-based" method is the dynamic evaluation of effector and regulatory T cell biology through their actual functional activity.