γδ T Cells Promote Anterior Chamber-Associated Immune Deviation and Immune Privilege through Their Production of IL-10

Abstract

Anterior chamber-associated immune deviation (ACAID) is a form of peripheral tolerance that is induced by introducing Ags into the anterior chamber (AC) of the eye, and is maintained by Ag-specific regulatory T cells (Tregs). ACAID regulates harmful immune responses that can lead to irreparable injury to innocent bystander cells that are incapable of regeneration. This form of immune privilege in the eye is mediated through Tregs and is a product of complex cellular interactions. These involve F4/80+ ocular APCs, B cells, NKT cells, CD4+CD25+ Tregs, and CD8+ Tregs. γδ T cells are crucial for the generation of ACAID and for corneal allograft survival. However, the functions of γδ T cells in ACAID are unknown. Several hypotheses were proposed for determining the functions of γδ T cells in ACAID. The results indicate that γδ T cells do not cause direct suppression of delayed-type hypersensitivity nor do they act as tolerogenic APCs. In contrast, γδ T cells were shown to secrete IL-10 and facilitate the generation of ACAID Tregs. Moreover, the contribution of γδ T cells ACAID generation could be replaced by adding exogenous recombinant mouse IL-10 to ACAID spleen cell cultures lacking γδ T cells.

Emerging concepts in CD8+ T regulatory cells

“…Although γδ T cells can act as APC in other settings [21], they do not participate in antigen presentation in ACAID, and instead they serve as important sources of IL-10 within the splenic milieu [22]. γδ T cell-derived IL-10 is required for the induction of ACAID CD8 + T regs, as reconstitution of γδ TCR −/− mice with γδ T cells from IL-10 −/− mice fails to restore ACAID CD8 + T regs, while reconstitution with γδ T cells from IL-10 competent mice does.…”

Thein vitro-Inductionof Type II Collagen-Specific Immune Tolerance in BALB/C Mice

“…We used an in vitro spleen cell culture system that we had previously used to generate Tregs that express the same properties and surface markers as Tregs produced in vivo (2,6). ACAID APCs (5x 10 6 ) , specific to CII, were added to a 100 mm petri dish containing 5x 10 7 spleen cells harvested from normal Balb/c mice and the culture was incubated for 5-7 days at 37°C before testing for the presence ofTregs.…”

“…ACAID APCs were generated in vitro as described previously (2,6). Ocular-like APCs from Balb/c mice were generated as described before (12).…”

“…Professional APCs can be immunogenic or tolerogenic depending on the involvement of unique cytokines that impact their maturation and activation, such as the immunosuppressive cytokines IL-I 0 and TGF-~that push towards the tolerogenic type (4,5). The in vitro culture of F4/80+ macrophages with antigens in the presence ofTGF-~2 could lead to the generation of ocular-like ACAID APCs, that induce antigen-specific immune tolerance when injected into experimental mice (2,6).…”

“…In order to obtain this potent antigen-specific peripheral immune tolerance, ACAID involves intricate multicellular communications between the eye-derived F4/80+ antigen presenting cells (APCs), splenic T cells, marginal zone B cells, NKT cells, and yo T cells (l). ACAID is characterized by the negative regulation of systemic Th 1 responses and of delayed type hypersensitivity (DTH) responses (2). This is achieved through professional APCs that induce the generation of afferent and efferent T regulatory cells (Tregs) (3), which could potentially be used to curb T-helper cell responses in autoimmune diseases.…”