The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help.

Fulcher, DA; Lyons, A. Bruce; Korn, SL; Cook, Matthew C.; Koleda, C; Parish, Christopher R.; Groth, Barbara Fazekas de St; Basten, Antony

doi:10.1084/jem.183.5.2313

Cited by 233 publications

(192 citation statements)

References 51 publications

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“…Although anergy is principally sufficient to incapacitate autoreactive B cells, its reported dependence on continuous antigenic stimulation via the BCR [9,30] may cause it to fail when antigen is lost. Anergy of B cells against systemic antigen may also be broken by autoreactive CD4 + Th cells as shown in transgenic systems using HEL [31] or hemagglutinin [32] as systemic autoantigens. Our findings are compatible with these previous findings by others, because also in ROH high mice some autoreactive CD4 T cell help was present.…”

Section: Discussionmentioning

confidence: 99%

CD25⁺ T_reg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

Ludwig‐Portugall¹,

Hamilton‐Williams²,

Gotot³

et al. 2009

Eur J Immunol

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To study B-cell tolerance against non-lymphoid tissue autoantigens, we generated transgenic rat insulin promoter (RIP)-OVA/hen egg lysozyme (HEL) mice expressing the model antigens, OVA and HEL, in pancreatic islets. Their vaccination with OVA or HEL induced far less auto-Ab titers compared with non-transgenic controls. Depletion of CD25 + cells during immunization completely restored auto-Ab production, but did not affect antibodies against a foreign control antigen. Depletion at later time-points was not effective. OVA-specific CD25 + FoxP3 + T reg were more frequent in the autoantigen-draining pancreatic LN than in other secondary lymphatics of RIP-OVA/HEL mice. Consistently, B cells were suppressed in that LN and also in the spleen, which is known to concentrate circulating antigen, such as the antigens used for vaccination. Suppression involved preventing expansion of autoreactive B cells in response to autoantigen, reducing antibody production per B-cell and isotype changes. These findings demonstrate that CD25 + T reg suppress auto-Ab production against non-lymphoid tissue antigens in an antigenspecific manner.Key words: Auto-antibodies . B cells . Tolerance . Transgenic mice . T reg IntroductionAutoreactive B cells are controlled by a series of self-tolerance mechanisms. The first checkpoint incapacitates B cells of high affinity to autoantigen in the bone marrow, by receptor editing [1,2] or central deletion [1][2][3][4]. Self-reactive low-affinity B cells enter the periphery and can constitute up to 5-20% of circulating mature B cells in healthy individuals [5,6]. Therefore, further peripheral checkpoints exist, such as deletion [1,2,7] or anergy [1,8,9]. Anergic B cells are arrested in the transitional T2 developmental stage, followed by their death [10]. B cells also die in response to continuous antigen binding [11] and BCR signaling [9].Auto-Ab production by autoreactive B cells that survive these checkpoints can be avoided by extrinsic regulation [1], like the absence of T cell help resulting from central T-cell tolerance, which appears to be more efficient than central B-cell tolerance [12]. Th cells are required for B-cell survival [1], class switching, Ig synthesis and somatic hypermutation [6,13,14]. The latter process not only further increases BCR diversity but may also generate self-reactive B cells, with an even higher risk for autoimmunity, because after somatic hypermutation, B cells are long-lived and produce high-affinity Ab [15]. Thus, additional tolerance mechanisms seem to be required for maintaining peripheral B-cell tolerance, such as active suppression [6].In addition to T-cell suppression, T reg have also been proposed to control antibody production, since auto-Ab titers in B-cellmediated disease models were associated with decreased numbers or functionality of T reg , and because depletion of T reg aggravated disease [16,17]. The role of T reg in antibody production against non-lymphoid tissue autoantigens is unresolved. In rat insulin promoter (RIP)-mOVA mice expressing the mo...

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Section: Discussionmentioning

confidence: 99%

CD25⁺ T_reg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

Ludwig‐Portugall¹,

Hamilton‐Williams²,

Gotot³

et al. 2009

Eur J Immunol

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“…with 5 Â 10 5 CFU rBCG strains. At 14 days post-vaccination organs were processed and the CFSE profile of dividing cells analyzed as described [39].…”

Section: Adoptive Transfer Experimentsmentioning

confidence: 99%

Modulation of pulmonary DC function by vaccine‐encoded GM‐CSF enhances protective immunity against Mycobacterium tuberculosis infection

et al. 2009

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The rational design of new vaccines engineered to target key components of the host immune response is crucial to aid control of important infectious diseases such as tuberculosis. In this report, we determined whether modifying the function of pulmonary APC could improve protection against infection with Mycobacterium tuberculosis. Targeted delivery to the lung of the cytokine GM‐CSF, expressed by the Mycobacterium bovis BCG vaccine strain, increased pulmonary DC numbers and secretion of the immunoregulatory cytokine IL‐12, compared with parental BCG immunization. This impact on APC number by BCG:GM‐CSF resulted in accelerated priming of antigen‐specific CD4+ T cells in the mediastinal lymph nodes and increased migration of activated CD4+ T cells into the lung. i.n. administration of BCG:GM‐CSF resulted in significantly increased protection against M. tuberculosis infection compared with mice vaccinated with BCG alone. BCG:GM‐CSF exhibited an improved safety profile, as immunodeficient RAG1−/− mice vaccinated i.n. with BCG:GM‐CSF survived significantly longer than control BCG‐vaccinated mice. These data demonstrate that manipulating immune cells in the lung by BCG‐based delivery of GM‐CSF can assist the development of protective mucosal immunity against pulmonary bacterial infection.

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“…Most Agspecific B cells exposed to oligovalent Ag, however, become hyporesponsive (anergic); they secrete less Ig than naive B cells in response to in vitro stimulation with LPS or Th cells, and proliferate poorly in response to anti-Ig Ab stimulation (9). These hyporesponsive B cells lose all or most of their mIgM (8, 10 -12) and are deleted within a few days after migrating to the spleen (12)(13)(14)(15), before they acquire the mature B cell phenotype. The small percentage of Ag-specific B cells that survives to maturity in the presence of oligovalent Ag predominantly does so by further decreasing its responsiveness to Ag, either by undergoing receptor editing (8) or by down-regulating its expression of mIgD as well as mIgM (12).…”

Section: Il-4 Promotesmentioning

confidence: 99%

IL-4 Promotes Stat6-Dependent Survival of Autoreactive B Cells In Vivo Without Inducing Autoantibody Production

Morris

Dragula

Finkelman

2002

The Journal of Immunology

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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.

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The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help.

Cited by 233 publications

References 51 publications

CD25⁺ T_reg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

CD25⁺ T_reg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

Modulation of pulmonary DC function by vaccine‐encoded GM‐CSF enhances protective immunity against Mycobacterium tuberculosis infection

IL-4 Promotes Stat6-Dependent Survival of Autoreactive B Cells In Vivo Without Inducing Autoantibody Production

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The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help.

Cited by 233 publications

References 51 publications

CD25+ Treg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

CD25+ Treg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

Modulation of pulmonary DC function by vaccine‐encoded GM‐CSF enhances protective immunity against Mycobacterium tuberculosis infection

IL-4 Promotes Stat6-Dependent Survival of Autoreactive B Cells In Vivo Without Inducing Autoantibody Production

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CD25⁺ T_reg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens

CD25⁺ T_reg specifically suppress auto‐Ab generation against pancreatic tissue autoantigens