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Mechanisms of the Natural Reactivity of Lymphocytes from Noninfected Individuals to Membrane-Associated Leishmania infantum Antigens¹

Atfa Sassi^*, Beya Larguèche-Darwaz^*, Alexis Collette, Adrien Six, Dhafer Laouini^*, Pierre André Cazenave and Koussay Dellagi^2,*

^* Laboratoire d’Immunopathologie, Vaccinologie et Génétique Moléculaire et Laboratoire International Associé Bioingénierie Moléculaire, Institut Pasteur de Tunis, Tunis, Tunisia; and Unité d’Immunophysiopathologie Infectieuse, Centre National de la Recherche Scientifique Unité de Recherche Associée 1961, Institut Pasteur, Paris, France

Membrane-associated Leishmania Ags (MLA) or soluble Leishmania Ags were used in vitro to stimulate cord blood or PBMC from healthy donors noninfected by Leishmania parasites. MLA, but not soluble Leishmania Ags, constantly induce strong proliferation of cord blood mononuclear cells and PBMC from noninfected individuals. Responding cells are CD3⁺, CD4⁺, TCR⁺, CD45RO⁺, and CD45RA⁺ and secrete IFN- and IL-10, but not IL-4. MLA do not activate NK cells nor NKT cells. Membrane Ags also induce purified macrophages from noninfected individuals to secrete IL-10 and TNF-, but have no effect on IL-1 or IL-12 secretion. The effects of MLA are proteinase K-sensitive and resistant to lipid extraction. The lymphoproliferative responses are inhibited by anti-HLA-DR Abs and require Ag processing by APCs, excluding that the biological effect of MLA could be attributed to a superantigen. Finally, TCR repertoire analysis shows that the T cell expansion induced by MLA uses TCR with various variable segment rearrangements and CDR3 lengths, features much more characteristic to those observed with a polyclonal activator than with a conventional Ag. These results suggest a particular mechanism developed during the host’s natural response to Leishmania parasites that allows direct activation of naive CD4 lymphocytes by parasite membrane-associated Ags.