title: Toll-like receptor 4-activated B cells out-compete Toll-like receptor 9-activated B cells to establish peripheral immunological tolerance.
abstract: B-cell-induced peripheral T-cell tolerance is characterized by suppression of T-cell proliferation and T-cell-dependent antibody production. However, the cellular interactions that underlie tolerance induction have not been identified. Using two-photon microscopy of lymph nodes we show that tolerogenic LPS-activated membrane-bound ovalbumin (mOVA) B cells (LPS B cells) establish long-lived, highly motile conjugate pairs with responding antigen-specific OTII T cells but not with antigen-irrelevant T cells. Treatment with anti-CTLA-4 disrupts persistent B-cell-T-cell (B-T) contacts and suppresses antigen-specific tolerance. Nontolerogenic CpG-activated mOVA B cells (CpG B cells) also form prolonged, motile conjugates with responding OTII T cells when transferred separately. However, when both tolerogenic and nontolerogenic B-cell populations are present, LPS B cells suppress long-lived CpG B-OTII T-cell interactions and exhibit tolerogenic dominance. Contact of LPS B cells with previously established B-T pairs resulted in partner-swapping events in which LPS B cells preferentially migrate toward and disrupt nontolerogenic CpG mOVA B-cell-OTII T-cell pairs. Our results demonstrate that establishment of peripheral T-cell tolerance involves physical engagement of B cells with the responding T-cell population, acting in a directed and competitive manner to alter the functional outcome of B-T interactions.
authors.affiliation: Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.
authors.forename: Melanie P
authors.initials: MP
authors.lastname: Matheu
authors.forename: Yan
authors.initials: Y
authors.lastname: Su
authors.forename: Milton L
authors.initials: ML
authors.lastname: Greenberg
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Blanc
authors.forename: Ian
authors.initials: I
authors.lastname: Parker
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cahalan
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000276:immunology; D005434:Flow Cytometry; D008198:Lymph Nodes / Q000276:immunology*; D051379:Mice; D010047:Ovalbumin / Q000378:metabolism; D061166:Peripheral Tolerance / Q000276:immunology*; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D010047:Ovalbumin