IL-4 promotes Stat6-dependent survival of autoreactive B cells in vivo without inducing autoantibody production.
Persistent cross-linking of hen egg lysozyme (HEL)-specific B cell membrane Ig (mIg) in double transgenic mice that express soluble HEL as a self Ag (HEL-Ig mice) decreases B cell mIgM expression, responsiveness, and life span. Because in vitro treatment with IL-4 inhibits T cell apoptosis through a Stat6-independent mechanism, increases mIg expression, and suppresses activation-induced B cell death, we studied IL-4 effects on B cell mIg expression, survival, and Ab secretion in Stat6-sufficient and deficient HEL-Ig mice. IL-4 treatment nearly normalized B cell number and greatly increased the percentage of mature B cells in HEL-Ig mice, but failed to normalize mIgM expression or spontaneous LPS-induced IgM secretion. IL-4 effects on B cell survival and maturation were CD4(+) T cell independent, but Stat6 dependent, and did not involve receptor editing. IL-4 had to be present while B cells were generated to have a detectable effect on autoreactive B cell survival; however, the survival of B cells generated in the presence of IL-4 was substantially increased even after IL-4 was withdrawn. These observations suggest that: 1) activation-induced B cell death and anergy are independent processes; 2) B cells that survive to maturity develop increased resistance to Ag-induced deletion; and 3) IL-4 promotes B and T cell survival through different mechanisms.
Morris
Suzanne C
SC
Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA. morrissc@email.uc.edu
Dragula
Nanette L
NL
Finkelman
Fred D
FD
D000818:Animals; D000911:Antibodies, Monoclonal; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000235:genetics; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002645:Chickens; D017635:Clonal Anergy; D005260:Female; D007075:Immunoglobulin M / Q000096:biosynthesis; D015847:Interleukin-4 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics / Q000276:immunology; D017393:RNA Editing; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis / Q000235:genetics; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001324:Autoantigens; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D009113:Muramidase