Suppression by CD4+CD25+ Regulatory T Cells Is Dependent on Expression of Heme Oxygenase-1 in Antigen-Presenting Cells

Abstract

Historically, heme oxygenase-1 (HO-1) has been viewed as a cytoprotective protein, ameliorating the effects of inflammatory cellular damage. The demonstration, however, of a beneficial role for HO-1 in allograft protection from acute and chronic rejection, 1-3 strongly suggests an important function of this enzyme in both innate and adaptive immune responses. In the original description of a mouse model of HO-1 deficiency, Poss and Tonegawa 4 noted an age-related overgrowth of the CD4 ϩ T-cell population, suggesting impaired regulation of T-cell proliferation. Our previous work assessing immune function in HO-1 Ϫ/Ϫ mice supported this notion because it showed a predominance of Th1-type cytokine secretion [eg, interleukin (IL)-1, interferon-␥, tumor necrosis factor-␣, IL-6] from splenocytes after polyclonal stimulation of T cells, implying that HO-1 activity is important in modulation of lymphocyte activation.5 This is of particular interest given reports that HO-1 is constitutively expressed in the CD4 ϩ CD25 ϩ subset of Treg cells, 6 and that HO-1 levels increase even further after T-cell stimulation.7 Furthermore, the report by Song and colleagues 8 demonstrated that carbon monoxide (CO), a byproduct of HO activity, has a very strong inhibitory effect on CD3-activated T-cell proliferation. Previously, we proposed a hypothetical model for the immunomodulatory effects of HO-1 in the maintenance of peripheral tolerance based on then available evidence that CO produced in regulatory T (Treg) cells may be an integral component of the suppression of T-cell activation by Treg cells in the presence of effector T (Teff) cells and antigen-presenting cells (APCs). 9The purpose of the present study was to analyze the role of HO-1 in Treg-mediated suppression. As a first step, we performed a phenotypic analysis of lymphocytes obtained from the peripheral lymphoid organs of HO-1 Ϫ/Ϫ mice for potential abnormalities. In the second step, we explored the functional significance of these findings in a series of T-cell proliferation/suppression assays. Finally, we examined the possibility that HO-1 exSupported by the National Institutes of Health (grants K08 AI 57362 to M.H.K., and R01 DK 075532 and R01 HL068157 to A.A).

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

“…But a lack of HO-1 in the APC abrogated suppression and appeared to enhance proliferation. The same effect was observed when BMDC were used as APCs (55). These observations were consistent with an earlier report that induction of HO-1 in DC inhibits their ability to stimulate alloreactive T cells (39,112) and supported the concept that HO-1 has an importantly regulatory role in APC function.…”

Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation

“…However, we cannot exclude that the effects observed in pups pretreated with heme or with adoptively transferred Tregs are independent. Adoptive transfer of Tregs might reduce NEC severity simply by directly increasing the Treg population; while heme pretreatment might alter the immunoregulatory effects of Tregs through an induction of HO-1 expression in dendritic cells (DCs) as shown by George et al (31).…”

Immunoregulatory Effects of Stored Red Blood Cells

“…18,19 Dendritic cells treated with HO-1 and CO can inhibit ROS and the production of proinflammatory cytokines such as IL-12, IL-6, TNF-␣, and IFN type I. 19,20 Conversely, the antiinflammatory IL-10 cytokine is increased after HO-1 overexpression or CO, and CO alone has been shown to inhibit T-lymphocyte proliferation. 21 This has led to the proposal that HO-1 and CO may mediate immune tolerance by favoring the induction of master immunosuppressor cells, the so-called regulatory T cells (Tregs).…”