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CD8+CD122+ regulatory T cells (CD8+CD122+ Treg) are naturally occurring Treg that effectively suppress the proliferation and IFN-γ production of both CD8+ and CD4+ target cells. This study investigated the molecular mechanisms of the recognition of target cells by CD8+CD122+ Treg using an in vitro culture system that reconstitutes the regulatory action of these cells. Naive CD8+CD122+ Treg co-cultured with pre-activated T cells became active Treg that produced IL-10 and suppressed IFN-γ production from the target T cells. CD8+CD122+ Treg effectively suppressed the IFN-γ production of the target cells of syngeneic mouse strains but not of allogeneic mouse strains with incompatible MHC. By using MHC-congeneic mouse strains, MHC-restricted suppression by CD8+CD122+ Treg was further confirmed. The blockade of cell surface molecules either on the Treg or on the target cells by specific blocking antibodies indicated that H-2K, H-2D, αβTCR and CD8 were involved in the regulatory action but I-A and Qa-1 were not. These results indicate that CD8+CD122+ Treg recognize already-activated T cells via the interaction of conventional MHC class I–αβTCR and become active regulatory cells that produce IL-10 and suppress the target cells. [ABSTRACT FROM PUBLISHER]

CD8+CD122+ regulatory T cells are a newly identified, naturally occurring type of regulatory T cell that produce interleukin-10 (IL-10) and effectively suppress interferon-γ (IFN-γ) production from both CD8+ and CD4+ target cells. Molecular mechanisms responsible for the recognition of target cells by CD8+CD122+ regulatory T cells were investigated in this study by using an in vitro culture system that reconstitutes the regulatory action of these cells. CD8+CD122+ regulatory T cells did not produce IL-10 and did not suppress the IFN-γ production of allogeneic target T cells when they were stimulated by immobilized anti-CD3 antibody alone, but they clearly produced IL-10 and suppressed the IFN-γ production of target cells when stimulated by anti-CD3 plus anti-CD28-coated beads. IFN-γ production by major histocompatibility complex-class I-deficient T cells was also suppressed by CD8+CD122+ regulatory T cells stimulated with anti-CD3 plus anti-CD28 antibody but was not suppressed by cells stimulated by anti-CD3 alone. Experiments examining the blockade of cell surface molecules expressed on either the regulatory cells or the target cells by adding specific neutralizing antibodies in the culture indicated that CD80, CD86, and CD28 molecules were involved in the regulatory action, but cytotoxic T lymphocyte antigen-4, inducible costimulatory molecule (ICOS) and programmed death-1 (PD-1) molecules were not. Finally, CD8+CD122+ cells isolated from CD28-knockout (CD28−/−) mice showed no regulatory activity. These results indicate that CD8+CD122+ regulatory T cells recognize target T cells via the interaction of CD80/CD86–CD28 molecules to become active regulatory cells that produce suppressive factors such as IL-10. [ABSTRACT FROM AUTHOR]

We identified CD8+CD122+ regulatory T cells (Tregs) and demonstrated their importance in the maintenance of immune homeostasis and in the recovery from experimental autoimmune encephalomyelitis. In this paper, we show that CD8+CD122+ Tregs effectively prevent and cure colitis in a mouse model. In our experiments, colitis was induced in lymphocyte-deficient RAG-2-/- mice by transferring CD4+CD45RBhigh cells that were excluded with CD4+ Tregs. Cotransfer of CD8+CD122+ cells clearly suppressed the development of colitis, and this suppressive effect was similar to that of CD4+CD45RBlow cells that were mostly CD4+ Tregs. CD8+CD122+ cells obtained from IL-10-/- mice were unable to suppress colitis, indicating that IL-10 is an important effect-transmitting factor in the suppression of colitis. CD8+CD122+ cells showed a suppressive effect when they were transferred 4 wk after CD4+CD45RBhigh cells, indicating the therapeutic potential of CD8+CD122+ cells. A mixture of CD8+CD122+ cells and CD4+CD45RBlow cells was far more effective than single Tregs, indicating the synergistic effect of these Tregs. These overall findings demonstrate the potential role of CD8+ Tregs, and possibly together with CD4+ Tregs, in the medical care of inflammatory bowel disease patients. [ABSTRACT FROM AUTHOR]