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The Th2 Lymphoproliferation Developing in Lat^Y136F Mutant Mice Triggers Polyclonal B Cell Activation and Systemic Autoimmunity¹

Céline Genton^*, Ying Wang, Shozo Izui, Bernard Malissen, Georges Delsol^,¶, Gilbert J. Fournié^||, Marie Malissen^2, and Hans Acha-Orbea^2,3,*

^* Department of Biochemistry, University of Lausanne, Epalinges, Switzerland; Centre d’Immunologie de Marseille-Luminy, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de la Méditérranée, Marseille, France; Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; INSERM Unité 563, Centre de Physiopathologie de Toulouse-Purpa, Toulouse, F-31300 France; ^¶ Département Oncogénèse et Signalisation dans les Cellules Hématopoiétiques, Institut Fédératif de Recherche 30 and Laboratoire d’Anatomie Pathologique, Purpan’s Hospital, Toulouse F-31300, France; ^|| INSERM Unité 563, Centre de Physiopathologie de Toulouse-Purpan, Toulouse, F-31300 France; and ^# Département de Génétique Fonctionnelle des Maladies des Épithéliums, Institut Fédératif de Recherche 30, Purpan’s Hospital, Toulouse F-31300, France

Lat^Y136F knock-in mice harbor a point mutation in Tyr¹³⁶ of the linker for activation of T cells and show accumulation of Th2 effector cells and IgG1 and IgE hypergammaglobulinemia. B cell activation is not a direct effect of the mutation on B cells since in the absence of T cells, mutant B cells do not show an activated phenotype. After adoptive transfer of linker for activation of T cell mutant T cells into wild-type, T cell-deficient recipients, recipient B cells become activated. We show in vivo and in vitro that the Lat^Y136F mutation promotes T cell-dependent B cell activation leading to germinal center, memory, and plasma cell formation even in an MHC class II-independent manner. All the plasma and memory B cell populations found in physiological T cell-dependent B cell responses are found. Characterization of the abundant plasmablasts found in secondary lymphoid organs of Lat^Y136F mice revealed the presence of a previously uncharacterized CD93-expressing subpopulation, whose presence was confirmed in wild-type mice after immunization. In Lat^Y136F mice, B cell activation was polyclonal and not Ag-driven because the increase in serum IgG1 and IgE concentrations involved Abs and autoantibodies with different specificities equally. Although the noncomplement-fixing IgG1 and IgE are the only isotypes significantly increased in Lat^Y136F serum, we observed early-onset systemic autoimmunity with nephritis showing IgE autoantibody deposits and severe proteinuria. These results show that Th2 cells developing in Lat^Y136F mice can trigger polyclonal B cell activation and thereby lead to systemic autoimmune disease.

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