Regulatory mechanisms in immune responses to heterologous insulins. II. Suppressor T cell activation associated with nonresponsiveness in H-2b mice.

Jensen, Peter E.; Pierce, Carl W.; Kapp, Judith A.

doi:10.1084/jem.160.4.1012

Cited by 43 publications

(25 citation statements)

References 22 publications

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“…Moreover, primed mice that were boosted several times with INS failed to develop evidence of pancreatic infiltration beyond the occasional interstitial infiltration of mononuclear cells seen in control mice primed with CFA alone (41). The failure of the INS-CTL to induce diabetes cannot be attributed to the lack of CD4 ϩ helper T cells because they are activated by both BINS and HINS in CFA (1,16,17). It is not clear whether the failure to develop diabetes in B6 mice is due to a precursor frequency that is below the threshold to produce disease, expression of TCR with low avidity, the lack of other essential signals required to target the CTL to the pancreas, the cytokine profile of the INS-CTL, or other factors.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we reported that injection of PINS in CFA stimulated CD8 ϩ T cells that prevent the development of an Ab response in nonresponder B6 mice (1,2). Removal of the CD8 ϩ T cells revealed that radioresistant, CD4 ϩ helper T cells had been primed by PINS.…”

Section: Discussionmentioning

confidence: 99%

“…Insulin-specific (INS) CD4 ϩ T cells also have been cloned from BALB/c mice rendered nonresponsive to HINS by the pancreatic expression of the HINS transgene (17). In contrast to PINS, bovine insulin (BINS) induces an Ab response in B6 mice, and removal of CD8 ϩ T cells did not alter the helper activity of the remaining CD4 ϩ T cells (1 …”

Section: Any Investigators Have Reported That Exogenous Ag Activatementioning

confidence: 99%

“…For example, porcine insulin (PINS), 5 which fails to stimulate Ab responses in C57BL/6 mice, does so if radioresistant CD8 ϩ T cells are removed (1,2). Such suppressive activity has been puzzling because CD8 ϩ T cells recognize predominantly endogenous Ag that is processed via the MHC class I pathway.…”

Section: Any Investigators Have Reported That Exogenous Ag Activatementioning

confidence: 99%

“…Previously, we reported that injection of PINS in CFA stimulates CD8 ϩ T cells that prevent the development of an Ab response in nonresponder C57BL/6 (B6) mice (1,2). In addition, CD4 ϩ helper T cells have been cloned from nonresponder mice primed with PINS or human insulin (HINS) (16).…”

Section: Any Investigators Have Reported That Exogenous Ag Activatementioning

confidence: 99%

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Bovine and Human Insulin Activate CD8+-Autoreactive CTL Expressing Both Type 1 and Type 2 Cytokines in C57BL/6 Mice

Ma¹,

Ke²,

et al. 2000

The Journal of Immunology

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CD8+ T cells down-regulate a variety of immune responses. For example, porcine and human insulin do not stimulate Abs in C57BL/6 mice because CD8+ T cells inhibit CD4+ helper T cells. By contrast, bovine insulin induces Ab in C57BL/6 mice, and removal of CD8+ T cells does not alter this response. This raises the question of whether porcine, but not bovine, insulin activates CD8+ T cells or whether both insulins activate CD8+ T cells but CD4+ helper T cells are differentially inhibited by them. In this study, we show that insulin-specific CD8+ CTL can be cultured from C57BL/6 mice primed with either bovine or human insulin in CFA. Thus, exogenous Ags, besides OVA, induce CD8+ CTL when administered in an adjuvant, suggesting this is a typical response. These CTL are H-2Kb restricted and produce IL-5, IL-10, IFN-γ, and small amounts of IL-4, which is distinct from IFN-γ and TNF-α that are typically secreted by virus-specific CTL. Moreover, the CTL primed with either bovine or human insulin recognize an A-chain peptide that is identical to the mouse insulin sequence. That foreign proteins, which are closely related to self-proteins, activated autoreactive, CD8+ T cells in vivo is a novel finding. It raises the possibility that self-reactive CTL may be activated by cross-reacting Ags and once activated they might participate in autoimmunity. These results also suggest that down-regulation of insulin-specific responses by autoreactive CD8+ T cells is most likely due to the differential sensitivity of bovine and human insulin-specific CD4+ T cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Any Investigators Have Reported That Exogenous Ag Activatementioning

confidence: 99%

Section: Any Investigators Have Reported That Exogenous Ag Activatementioning

confidence: 99%

Section: Any Investigators Have Reported That Exogenous Ag Activatementioning

confidence: 99%

See 3 more Smart Citations

Bovine and Human Insulin Activate CD8+-Autoreactive CTL Expressing Both Type 1 and Type 2 Cytokines in C57BL/6 Mice

Ma¹,

Ke²,

et al. 2000

The Journal of Immunology

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Evidence for Th2 cell‐mediated suppression of antibody responses in transgenic, beef insulin‐tolerant mice

et al. 1995

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Clonal deletion, anergy and suppression have all been considered mechanisms of immunological tolerance. Although adoptive transfer of immunosuppression has been shown to occur in the periphery, particularly for transplantation tolerance, it has proven difficult to characterize this phenomenon further, due to the lack of suppressor T cell clones. To characterize tolerance towards a physiological soluble antigen, we constructed beef insulin (BI) transgenic (Tg) BALB/c (H-2d) mice, in which the BI transgene is expressed in pancreatic beta cells. These Tg mice were tolerant to BI immunization at the level of both humoral and cell-mediated immune responses. Adoptive transfer of splenocytes from Tg mice into normal syngeneic BALB/c mice demonstrated that the reduction in antibody production is regulated by transferred T cells. The cytokine profile of T cell clones obtained after selection in vitro demonstrated dominant Th1 clones from normal non-Tg mice and dominant Th2 clones from Tg mice. Some Th2 clones (CD4+) from Tg mice produced significant suppression of antibody production after adoptive transfer into normal syngeneic BALB/c mice. These data confirm the existence of Th2 regulatory T cells in vivo in a model of peripheral tolerance to a physiological soluble antigen as a potential mechanism for self tolerance.

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Tolerance is overcome in beef insulin‐transgenic mice by activation of low‐affinity autoreactive T cells

et al. 1996

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To gain insight into the factors controlling the maintenance or loss of T cell self tolerance we produced beef insulin (BI)-transgenic BALB/c mice. Transgenic mice express BI under control of the human insulin promoter and secrete physiological amounts of beef insulin. Although these mice are tolerant to BI, as evidenced by the lack of insulin-specific IgG antibody production following intraperitoneal immunization, tolerance is not complete. Footpad immunization results in a weak antigen-specific T cell proliferative response, indicating the presence of self-reactive BI-specific T cell in the periphery. These T cells are functional in vivo, providing support for IgG1, IgG2a, and IgG2b BI-specific antibody production, but require higher higher concentrations of antigen than nontransgenic T cells (both in vivo and following recall responses in vitro) to become activated. In vitro, BI-specific T cell proliferation in BI-transgenic mice can be largely restored by addition of interleukin-2, indicating that a significant component of T cell tolerance is mediated by anergy. To characterize the autoreactive T cells that become activated when tolerance is broken, BI-specific T cell hybridomas were generated from transgenic mice and compared to a panel of hybridomas previously derived from nontransgenic BALB/c mice. The majority of BI-transgenic hybridomas recognized the immunodominant A1-14 beef insulin peptide but with lower avidity than BALB/c hybridomas. Consistent with this, none of the dominant T cell receptor rearrangements found in the BALB/c BI-specific T cell receptor repertoire were found in the transgenic hybridomas. These results indicate that, despite evidence for clonal inactivation of many BI-specific T cells in BI-transgenic mice, loss of tolerance results from activation of low-affinity antigen-specific T cells that appear to have escaped this process.

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Regulatory mechanisms in immune responses to heterologous insulins. II. Suppressor T cell activation associated with nonresponsiveness in H-2b mice.

Cited by 43 publications

References 22 publications

Bovine and Human Insulin Activate CD8+-Autoreactive CTL Expressing Both Type 1 and Type 2 Cytokines in C57BL/6 Mice

Bovine and Human Insulin Activate CD8+-Autoreactive CTL Expressing Both Type 1 and Type 2 Cytokines in C57BL/6 Mice

Evidence for Th2 cell‐mediated suppression of antibody responses in transgenic, beef insulin‐tolerant mice

Tolerance is overcome in beef insulin‐transgenic mice by activation of low‐affinity autoreactive T cells

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