IL-5 promotes induction of antigen-specific CD4+CD25+ T regulatory cells that suppress autoimmunity

Abstract

Immune responses to foreign and selfAgs can be controlled by regulatory T cells (Tregs) expressing CD4 and IL-2R␣ chain (CD25). Defects in Tregs lead IntroductionBoth Ag-specific 1 and naive regulatory T cells (Tregs) 2-4 that control immune responses are mainly CD4 ϩ CD25 ϩ T cells 5 expressing transcription factor FOXP3. 6 Autoimmunity occurs with the breakdown in immune tolerance to self-Ag and can be because of a failure of natural Tregs (nTregs) produced by the thymus which prevent spontaneous autoimmune activation of CD4 ϩ CD25 Ϫ T effector cells by inhibiting APCs. 5 nTregs maintain immune homeostasis and are polyclonally expanded by IL-2. nTregs can suppress all immune responses, because they are not Ag specific. To fully suppress high ratios to effector lineage, CD4 ϩ CD25 Ϫ T cells are required, usually Ͼ 1:1; whereas the natural ratio of these cells in peripheral lymphoid tissues is tightly regulated to Ͻ 1:10. 7,8 There is ample evidence for Ag-specific Treg induction in vivo, including T-cell transfer of tolerance to specific autoantigen induced by immunization with autoantigen without complete Freund adjuvant (CFA), 9 the parabiosis of tolerance to autoimmunity from normal hosts, 10 and the epitope specificity of tolerance induction with an autoantigen. 11 Ag-specific CD4 ϩ CD25 ϩ Tregs have phenotypic and functional differences from the nTreg, recently reviewed by Hall et al. 12 Activated Tregs do not migrate from blood to lymph but express chemokine receptors and other ligands that promote their migration to sites of inflammation, where they control local inflammation. 12 Further, their action is not to inhibit APCs via CTLA4, but to inhibit or eliminate activated effector T cells and macrophages, by a variety of mechanisms. 12 To date, most studies focused on nTregs that suppress in a non-Ag-specific manner and must be present at high ratios with effector T cells to fully suppress an immune response. In autoimmune disease it would be desirable to induce Ag-specific Tregs that can suppress only the specific immune response at low ratios (Ͻ 1:10) to effector cells. 13 Specific immune tolerance, as occurs in adult rodents that accept an allograft long term, is mediated by Ag-specific CD4 ϩ CD25 ϩ Tregs that suppress at ratios Ͻ 1:10. 1,14,15 These alloantigen-specific Tregs are difficult to identify, because their survival depends on stimulation by both Ag 1,16 and T cell-derived cytokines. 17 IL-2 17 or IL-4 do not fully maintain activated Agspecific Tregs, but other cytokines such as IL-5 can. 3 In our studies, the initial activation of nTregs to alloantigenspecific Tregs occurred when they were cultured with specific alloantigens and either the T helper type 1 (Th1) cytokine IL-2 or the Th2 cytokine IL-4, but not other Th1 or Th2 cytokines. 3 Alloactivation of nTregs with IL-2 induces the receptor for the late Th1 cytokine IFN-␥ (Ifn␥r) but not the receptor for the Th2 cytokine ␤, Ifn␥r. 3 The selective induction of Il-5r␣ on Ag-activated Tregs that have been stimulated by IL-4, not IL-2, ra...

Helminth Products Protect against Autoimmunity via Innate Type 2 Cytokines IL-5 and IL-33, Which Promote Eosinophilia

“…To our knowledge, this study provides the first evidence that IL-5 may have a key role in helminth-induced attenuation of autoimmunity. Consistent with these findings, it has been reported that administration of recombinant IL-5 ameliorated experimental autoimmune neuritis in rats (42). However, the protective effect of exogenously administered IL-5 in this model appeared to be dependent on Tregs (42), suggesting species-specific differences in the response to IL-5.…”

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

“…In particular, treatment of experimental autoimmune neuritis with IL-5 markedly reduced the infiltration of CD4 + (Th1 and Th17) and CD8 + T cells, and macrophages in nerves with expansion of antigen-specific CD4 + CD25 + FoxP3 + Tregs. Moreover, the depletion of CD25 + Tregs or blocking of IL-4 abolished the benefits of IL-5 treatment [99]. Overall, the study suggested IL-5 therapy may be able to induce antigen-specific tolerance in autoimmune disease.…”

“…Tran et al [99] have shown that IL-5 is able to promote the induction of antigen-specific CD4 + CD25 + Tregs that suppress autoimmunity. In particular, treatment of experimental autoimmune neuritis with IL-5 markedly reduced the infiltration of CD4 + (Th1 and Th17) and CD8 + T cells, and macrophages in nerves with expansion of antigen-specific CD4 + CD25 + FoxP3 + Tregs.…”

T Cells

“…Ts2 cells have increased antigenspecific suppressor potency in vivo and in vitro, suppressing at ,1:10, whereas fresh nTregs only fully suppress at $1:1. We found that treatment with IL-5 promoted these cells to control autoimmunity (65) and transplant rejection (57). Tregs controlling Th2 responses express the transcription factor IRF4 (110).…”

“…They enhance antigen-specific suppressor capacity and can be further activated by specific antigen and IL-5 in the absence of IL-4 to Th2-like Tregs that have a very potent antigen-specific suppressor capacity. (57,65).…”