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The Th2 lymphoproliferation developing in LatY136F mutant mice triggers polyclonal B cell activation and systemic autoimmunity.
Journal of Immunology
Lat(Y136F) knock-in mice harbor a point mutation in Tyr(136) 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.
Adaptor Proteins, Signal Transducing/genetics, Adaptor Proteins, Signal Transducing/physiology, Amino Acid Substitution/genetics, Animals, Autoimmune Diseases/genetics, Autoimmune Diseases/immunology, B-Lymphocytes/cytology, B-Lymphocytes/immunology, Clone Cells, Lymphocyte Activation/genetics, Lymphoproliferative Disorders/genetics, Lymphoproliferative Disorders/immunology, Membrane Proteins/genetics, Membrane Proteins/physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Phenylalanine/genetics, Phosphoproteins/genetics, Phosphoproteins/physiology, Th2 Cells/immunology, Th2 Cells/pathology, Tyrosine/genetics
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