title: Self-tolerance checkpoints in CD4 T cells specific for a peptide derived from the B cell antigen receptor.
abstract: Linked recognition of Ag by B and T lymphocytes is ensured in part by a state of tolerance acquired by CD4 T cells to germline-encoded sequences within the B cell Ag receptor (BCR). We sought to determine how such tolerance is attained when a peptide from the BCR variable (V) region is expressed by small numbers of B cells as it is in the physiological state. Mixed bone marrow (BM) chimeras were generated using donor BM from mice with B cells that expressed a transgene (Tg)-encoded κ L chain and BM from TCR Tg mice in which the CD4 T cells (CA30) were specific for a Vκ peptide encoded by the κTg. In chimeras where few B cells express the κTg, many CA30 cells were deleted in the thymus. However, a substantial fraction survived to the CD4 single-positive stage. Among single-positive CA30 thymocytes, few reached maturity and migrated to the periphery. Maturation was strongly associated with, and likely promoted by, expression of an endogenous TCR α-chain. CD4(+) CA30 cells that reached peripheral lymphoid tissues were Ag-experienced and anergic, and some developed into regulatory cells. These findings reveal several checkpoints and mechanisms that enforce a state of self-tolerance in developing T cells specific for BCR V region sequences, thus ensuring that T cell help to B cells occurs through linked recognition of foreign Ag.
authors.affiliation: Integrated Department of Immunology, National Jewish Health, University of Colorado School of Medicine, Denver, CO 80206, USA.
authors.forename: Thiago
authors.initials: T
authors.lastname: Detanico
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Heiser
authors.forename: Katja
authors.initials: K
authors.lastname: Aviszus
authors.forename: Cristina
authors.initials: C
authors.lastname: Bonorino
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Wysocki
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D011828:Radiation Chimera; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; C111388:I-Ak antigen; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D010446:Peptide Fragments; D011947:Receptors, Antigen, B-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta