The Th2 lymphoproliferation developing in LatY136F mutant mice triggers polyclonal B cell activation and systemic autoimmunity.
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.
Genton
Céline
C
Department of Biochemistry, University of Lausanne, Chemin Des Boveresses 155, CH-1066 Epalinges, Switzerland.
Wang
Ying
Y
Izui
Shozo
S
Malissen
Bernard
B
Delsol
Georges
G
Fournié
Gilbert J
GJ
Malissen
Marie
M
Acha-Orbea
Hans
H
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D002999:Clone Cells; D008213:Lymphocyte Activation / Q000235:genetics*; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010649:Phenylalanine / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology*; D014443:Tyrosine / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D014443:Tyrosine; D010649:Phenylalanine