Human CD25+ Regulatory T Cells Maintain Immune Tolerance to Nickel in Healthy, Nonallergic Individuals

Abstract

We investigated the capacity of CD25+ T regulatory cells (Treg) to modulate T cell responses to nickel, a common cause of allergic contact dermatitis. CD4+ T cells isolated from the peripheral blood of six healthy, nonallergic individuals showed a limited capacity to proliferate in response to nickel in vitro, but responsiveness was strongly augmented (mean increment ± SD, 240 ± 60%) when cells were depleted of CD25+ Treg. Although CD25+ Treg were anergic to nickel, a small percentage up-regulated membrane CTLA-4 upon nickel exposure. CD25+ Treg strongly and dose-dependently inhibited nickel-specific activation of CD25− T lymphocytes in coculture experiments in a cytokine-independent, but cell-to-cell contact-dependent, manner. Approximately 30% of circulating CD25+ Treg expressed the cutaneous lymphocyte-associated Ag (CLA), and CLA+CD25+ Treg were more efficient than CLA−CD25+ cells in suppressing nickel responsiveness of CD25− T cells. The site of a negative patch test in response to nickel showed an infiltrate of CD4+CLA+ cells and CD25+ cells, which accounted for ∼20% of the total T cells isolated from the tissue. Skin-derived T cells suppressed nickel-specific responses of peripheral blood CD25− T cells. In addition, 60 ± 14% of peripheral blood CD25+ Treg expressed the chemokine receptor CCR7 and strongly inhibited naive T cell activation in response to nickel. Finally, CD25+ T cells isolated from peripheral blood of nickel-allergic patients showed a limited or absent capacity to suppress metal-specific CD4+ and CD8+ T cell responses. The results indicates that in healthy individuals CD25+ Treg can control the activation of both naive and effector nickel-specific T cells.

The Majority of Human Peripheral Blood CD4+CD25highFoxp3+ Regulatory T Cells Bear Functional Skin-Homing Receptors

“…The expression of skin-skewed homing receptors by peripheral blood CD4 ϩ CD25 ϩ T cells was previously reported by the other investigators (4,15); ϳ30% of CD4 ϩ CD25 ϩ T cells expressed CLA and 80% expressed CCR4. These studies, however, did not fractionate CD4 ϩ CD25 ϩ into their functionally distinct components.…”

“…This combination should allow Treg to enter from blood into secondary lymphoid tissues, suggesting a role for Treg in controlling systemic immunity as central memory T cells (14) at secondary lymphoid organs. In contrast, it has also been reported that unfractionated blood CD4 ϩ CD25 ϩ T cells express variable levels of peripheral tissue-homing receptors such as skin-associated CLA (4,15), CCR4 (16), and gut-associated ␣ 4 ␤ 7 integrin (17). In addition, Iellem et al (15) reported Treg express skin-vs gut-skewed homing receptors, describing that ϳ30% of CD4 ϩ CD25 ϩ T cells express CLA.…”

“…Because of its role as a critical interface with the external environment, a sophisticated cutaneous immune surveillance system has developed, wherein effective recruitment of skin-homing memory T cells from blood into skin is important (1). The role played by T regulatory cells (Treg) 4 in cutaneous immunity is not well understood. There is accumulating evidence that human CD4 ϩ CD25 ϩ Treg normally mediate peripheral tolerance by active immune suppression, and that altered function of CD4 ϩ CD25 ϩ Treg may be an important factor in a wide range of human autoimmune and inflammatory diseases, including inflammatory skin diseases (2)(3)(4)(5).…”

“…The role played by T regulatory cells (Treg) 4 in cutaneous immunity is not well understood. There is accumulating evidence that human CD4 ϩ CD25 ϩ Treg normally mediate peripheral tolerance by active immune suppression, and that altered function of CD4 ϩ CD25 ϩ Treg may be an important factor in a wide range of human autoimmune and inflammatory diseases, including inflammatory skin diseases (2)(3)(4)(5). Very recently, it has become clear that human peripheral blood CD4 ϩ CD25 ϩ T cells are heterogeneous and contain both CD4 ϩ CD25 high cells (2-3% of CD4 ϩ T cells) with potent Treg activity, as well as many more CD4 ϩ CD25 med nonregulatory cells (6).…”

Imunopatologia da dermatite de contato alérgica

“…106. 107 The mechanism of suppression induced by these cells is still under debate. In vitro studies suggest the need for cell-cell contact by interaction of the CTLA-4 of the regulatory cell with CD80 and CD86 for inactivation of effector TL.…”