Segregated Regulatory CD39+CD4+ T Cell Function: TGF-β–Producing Foxp3− and IL-10–Producing Foxp3+ Cells Are Interdependent for Protection against Collagen-Induced Arthritis

Abstract

Oral immunization with a Salmonella vaccine vector expressing enterotoxigenic E. coli colonization factor antigen I (CFA/I) can protect against collagen-induced arthritis (CIA) by dampening IL-17 and IFN-γ via enhanced IL-4, IL-10, and TGF-β. To identify the responsible regulatory CD4+ T cells making the host refractory to CIA, Salmonella-CFA/I induced CD39+CD4+ T cells with enhanced apyrase activity relative to Salmonella vector-immunized mice. Adoptive transfer of vaccine-induced CD39+CD4+ T cells into CIA mice conferred complete protection, while CD39−CD4+ T cells did not. Subsequent analysis of vaccinated FoxP3-GFP mice revealed the CD39+ T cells were composed of FoxP3-GFP− and FoxP3-GFP+ subpopulations. Although each adoptively transferred Salmonella-CFA/I-induced FoxP3− and FoxP3+CD39+CD4+ T cells could protect against CIA, each subset was not as efficacious as total CD39+CD4+ T cells, suggesting their interdependence for optimal protection. Cytokine analysis revealed FoxP3− CD39+CD4+ T cells produced TGF-β, and FoxP3+CD39+CD4+ T cells produced IL-10, showing a segregation of function. Moreover, donor FoxP3-GFP− CD4+ T cells converted to FoxP3-GFP+ CD39+CD4+ T cells in the recipients, showing plasticity of these regulatory T cells. TGF-β was found to be essential for protection since in vivo TGF-β neutralization reversed activation of cAMP-response element-binding protein (CREB) and reduced the development of CD39+CD4+ T cells. Thus, CD39 apyrase-expressing CD4+ T cells stimulated by Salmonella-CFA/I are composed of TGF-β-producing FoxP3− CD39+CD4+ T cells and support the stimulation of IL-10-producing FoxP3+ CD39+CD4+ T cells.

A commensal bacterial product elicits and modulates migratory capacity of CD39+CD4 T regulatory subsets in the suppression of neuroinflammation

“…17,[29][30][31][32][33][34][35] Our work and others show that within CD4 T cells, CD39 is a marker that delineates regulatory subsets independent of Foxp3. 36,37 It can be inferred that CD39 + CD4 T cells may comprise diverse regulatory subsets, including the canonical Foxp3 + CD4 Tregs, IL-10-secreting T regulatory type 1 (Tr1) cells and TGF-β-secreting T helper 3 (Th3) cells. The profile of chemokine receptors on CD39 + CD4 T cells suggests this postulation.…”

An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling

“…It has been reported that CD39 + Foxp3 + CD4 Tregs but not CD39 − Foxp3 + CD4 Tregs can effectively suppress Th17 45 . However, several studies indicate that CD39 + CD4 T cell is in itself a regulatory subset regardless of Foxp3 46,47 . It is speculated that CD39 + CD4 T cell consists of both Foxp3 + Tregs and Tr1 cells.…”

Interleukin‐6 Receptor Blockade Enhances CD39+ Regulatory T Cell Development in Rheumatoid Arthritis and in Experimental Arthritis

“…FoxP3ϩCD39ϩ Treg cells are impaired in patients with multiple sclerosis (33). Conversely, the CD39ϩ Treg cell population expands during remission of multiple sclerosis and after antiinflammatory treatment in CIA (46,47). Moreover, a very recent study has shown that an efficient therapy based on stem cell adoptive transfer mostly depended on CD39/CD73 signals and partially on the induction of CD4ϩCD39ϩFoxP3ϩ Treg cells in CIA (48).…”