Effects of T3 and rearing temperature on growth and skeletal myosin heavy chain isoform transition during early development in the salmonid Salvelinus alpinus (L.)

Rearing of 1-year-old Arctic charr (Salvelinus alpinus) at 12°C, as well as the administration of 50 or 75 mgT₃/kg feed, accelerated the neonatal to adult fast myosin heavy chain transition, but the effect of temperature was more dramatic than the effect of T₃ administration. The endogenous plasma levels of T₃ in charrs reared at 12°C were higher than those of analogous groups reared at natural temperature, which in the period under study was between 0.5 and 12°C. As in other species, T₃ seemed to play a role in the regulation of the neonatal to adult fast myosin isoform transition by down-regulating the levels of the neonatal and increasing the levels of an adult fast myosin heavy chain. Temperature seemed to accelerate this transition at least, but not only, by inducing an increase in the endogenous levels of T₃ in the Arctic charr.     

Persistence of physiological self antigen is required for the regulation of self tolerance

Endogenous Ag requirement for induction and maintenance of T cell tolerance has been extensively investigated in mice that express a transgenic Ag and/or its cognate transgenic TCR. In contrast, studies on tolerance for physiologically expressed self Ag and normal T cells are limited. Herein, we showed that the murine ovarian-specific ZP3 Ag is detectable from birth. Tolerance to ZP3 is detected in female relative to male mice. In comparison to males, 100-fold more ovarian peptide (pZP3) is required to elicit a comparable pathogenic response in females. Female tolerance to pZP3 was dependent on the presence of endogenous ovarian Ag, because neonatal ovariectomy converted the female response to that of males. Moreover, in female mice that were ovariectomized from the ages of 1-6 wk, the pZP3 responses were enhanced to the male level if ovaries were removed up to 7 days, but not 3 days, before adult challenge with pZP3. Thus, the physiologically expressed ZP3 Ag induces tolerance to pZP3, and the maintenance of tolerance is critically dependent on the continuous presence of the endogenous ovarian Ag. In contrast, exposure to endogenous ovarian Ag confined to the neonatal period is insufficient for the induction and maintenance of tolerance to ZP3.     

TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice

In previous studies, we have shown that murine CD4+CD25+ regulatory T cells produce high levels of TGF-beta1 in a cell surface and/or secreted form, and blockade of such TGF-beta1 by anti-TGF-beta curtails the ability of these cells to suppress CD25- T cell proliferation and B cell Ig production in in vitro suppressor assays. In further support for the role of TGF-beta1 in suppression by CD4+CD25+ T cells, we show in this study that another TGF-beta1-blocking molecule, recombinant latency-associated peptide of TGF-beta1 (rLAP), also reverses suppression by mouse CD4+CD25+ T cells as well as their human counterparts, CD4+CD25(high) T cells. In addition, we show that CD25- T cells exposed to CD4+CD25+ T cells in vitro manifest activation of Smad-2 and induction of CD103, the latter a TGF-beta-inducible surface integrin. In further studies, we show that while CD4+CD25+ T cells from TGF-beta1-deficient mice can suppress CD25- T cell proliferation in vitro, these cells do not protect recipient mice from colitis in the SCID transfer model in vivo, and, in addition, CD4+LAP+, but not CD4+LAP- T cells from normal mice protect recipient mice from colitis in this model. Together, these studies demonstrate that TGF-beta1 produced by CD4+CD25+ T cells is involved in the suppressor activity of these cells, particularly in their ability to regulate intestinal inflammation.     

Endogenous oocyte antigens are required for rapid induction and progression of autoimmune ovarian disease following day-3 thymectomy

Female (C57BL/6xA/J)F(1) mice undergoing thymectomy on day 3 after birth (d3tx) developed autoimmune ovarian disease (AOD) and autoimmune disease of the lacrimal gland. As both were prevented by normal adult CD25(+) T cells, regulatory T cell depletion is responsible for d3tx diseases. AOD began as oophoritis at 3 wk. By 4 wk, AOD progressed to ovarian atrophy with autoantibody response against multiple oocyte Ag of early ontogeny. The requirement for immunogenic endogenous ovarian Ag was investigated in d3tx female mice, d3tx male mice, and d3tx neonatally ovariectomized (OX) females. At 8 wk, all mice had comparable lacrimalitis but only those with endogenous ovaries developed AOD in ovarian grafts. The duration of Ag exposure required to initiate AOD was evaluated in d3tx mice OX at 2, 3, or 4 wk and engrafted with an ovary at 4, 5, or 6 wk, respectively. The mice OX at 2 wk did not have oophoritis whereas approximately 80% of mice OX at 3 or 4 wk had maximal AOD, thus Ag stimulus for 2.5 wk following d3tx is sufficient. AOD progression requires additional endogenous Ag stimulation from the ovarian graft. In mice OX at 3 wk, ovaries engrafted at 5 wk had more severe oophoritis than ovaries engrafted at 6 or 12 wk; moreover, only mice engrafted at 5 wk developed ovarian atrophy and oocyte autoantibodies. Similar results were obtained in mice OX at 4 wk. Thus endogenous tissue Ag are critical in autoimmune disease induction and progression that occur spontaneously upon regulatory T cell depletion.     

Retargeting T cell-mediated inflammation: a new perspective on autoantibody action

To understand the pathogenesis of organ-specific autoimmune disease requires an appreciation of how the T cell-mediated inflammation is targeted, and how the organ function is compromised. In this study, autoantibody was documented to influence both of these parameters by modulating the distribution of T cell-mediated inflammation. The murine autoimmune ovarian disease is induced by immunization with the ZP3330-342 peptide of the ovarian zona pellucida 3 glycoprotein, ZP3. Passively transferred or actively induced Ab to ZP3335-342 bound to the zona pellucida in the functional and degenerative ovarian follicles, and the ovaries remained histologically normal. Transfer of ZP3330-342 peptide-specific T cells targeted the degenerative follicles and spared the functional follicles, and the resultant interstitial oophoritis was associated with unimpaired ovarian function. Unexpectedly, the coexistence of ZP3330-342 peptide-specific T cells and zona-bound autoantibody led to a dramatic translocation of the ovarian inflammation to the growing and mature ovarian follicles, with destruction of the ovarian functional unit. Ab retargeted both Th1-induced mononuclear inflammation and Th2-induced eosinophilic inflammation, and retargeting was induced by murine and rat polyclonal Abs to multiple distinct native B cell determinants of the zona pellucida. Therefore, by reacting with the native determinants in tissue Ag, Ab alters the distribution of T cell-mediated inflammation, and results in destruction of the functional units of the target organ. We propose that this is a clinically important and previously unappreciated element of Ab action in autoimmune disease.