Suppressive Effects on CD4T Cells but not CD8T Cells

IL-10 Acts on CD8+T Cells to Stimulate Survival

APCs and lymphocytes are the primary targets of IL-10. IL-10 suppresses proinflammatory cytokine production and the antigen presenting capacity of monocytes/macrophages and dendritic cells.2 IL-10 costimulates proliferation and differentiation of B cells,38 which is important in inducing production of antibodies in the setting of intestinal parasites, neutralization of bacterial toxins, and in local mucosal defense. In addition, the direct immunological effects of

Figure 1. IL-10 is a pleiotrophic cytokine regulating immune effector cells and modulating inflammation to limit host tissue injury. IL-10 has two diametrically opposed and separate functional activities on effector cells. IL-10 stimulates and maintains the cytolytic and effector function of NK cells and CD8+T cells. In contrast, it limits naïve CD4+T cell activation and Th1 cell evolution, inducing abrogates the maturation of DCs, resulting in downregulation of costimulatory molecules and IL-12 production. These desparate effects ofIL-10, orchestrate the balance of stimulatory and suppressive effects for many types of effector cells, dependent on the phase of the immune/inflammatory response.

Figure 1. IL-10 is a pleiotrophic cytokine regulating immune effector cells and modulating inflammation to limit host tissue injury. IL-10 has two diametrically opposed and separate functional activities on effector cells. IL-10 stimulates and maintains the cytolytic and effector function of NK cells and CD8+T cells. In contrast, it limits naïve CD4+T cell activation and Th1 cell evolution, inducing abrogates the maturation of DCs, resulting in downregulation of costimulatory molecules and IL-12 production. These desparate effects ofIL-10, orchestrate the balance of stimulatory and suppressive effects for many types of effector cells, dependent on the phase of the immune/inflammatory response.

IL-10 on these populations include the regulation of Th1/Th2 balance. IL-10 sometimes promotes the development of type 2 cytokines by inhibiting the IFN-y production of CD4+ and CD8+ T lymphocytes particularly via suppression of IL-12 synthesis in accessory and costimulatory molecule-expressing can be a substantial suppressor of the cellular immune response.

Besides the dominant indirect impact via the APCs, IL-10 exerts suppressive effects on naïve T cells (Fig. 1).2,39-41 In contrast, IL-10 directly enhances not only NK cell but also CD8+ cytotoxic T lymphocytes (CTL) cytotoxicity.42-45 IL-10 has stimulatory effects on CD8+ T cells and induces their recruitment, cytotoxic activity, and proliferation. IL-10 does not exert potent direct inhibitory effects on CD8+T cells, but rather can activate CD8+T cells under many conditions.

IL-10 enhances the proliferative responses of murine IL-2- and IL-4-activated CD8+T cells and rescues T cells from apoptotic cell death.46,47 As such, IL-10 enhances the effects of antitumor CD8+T cells in vivo, leading to the reduced growth of immunogenic tumors.45,48-50 Administration of high doses of IL-10 injections mediates rejection of tumors with contrasting effects on CD4+ and CD8+ T cells that result in either immune dampening or immune potentiation of these individual cell types in situ, respectively.45 Both interferon family members, IL-10 and IFN-y, may have immunostimulatory or immunoregulatory effects leading to exacerbation of GVHD or down-regulation of this posttransplantation complications.34,51 In some

GVHD models, IL-10 may cause exacerbation probably through effects mediated by both NK and activated CD8+ T cells. IL-10 promotes IL-2-independent growth of activated CD8+T cells in the absence of additional apparent costimulatory signals in autologous and allogeneic GVHD.34'51

IL-10 Induces Nonresponsiveness in CD4+ T Cells

As described above, IL-10 positively stimulates CD8+ T cells under some conditions. In contrast, IL-10 has suppressive effects on CD4+T cells. IL-10 directly inhibits proliferation and cytokine/chemokine-synthesis of CD4+T cells. This includes IL-2, IFN-y, IL-4 and IL-5 production as well as CXCR4 production and chemotaxis in response to the CXCR4 ligand SDF1.2'52-54 IL- 10 inhibits both the Th1-type and the Th2-type responses of CD4+T cells (Fig. 1). Naive CD4+T cells are the major targets of IL-10; whereas activated and memory T cells seem to be rather insensitive.32 The presence of IL-10 during the activation of CD4+T cells results in the development of a regulatory phenotype. Such regulatory cells are characterized by weak proliferation, a failure to produce IL-2, and expression of a specific cytokine profile (IL-10+, IFN-Y+, IL-4-, IL-5-) after repeated stimulation.32,55-57 IL-10 strongly inhibits cytokine production and proliferation of CD4+T cells or CD4+T cell clones via its downregulatory effects on APC function. Either CD4+ T cells cultured in the presence of IL-10, or IL-10-treated APCs become nonresponsive and fail to proliferate or produce inflammatory cytokines. The role of IL-10 in induction and maintenance of nonresponsiveness or anergy were studied in anti-tumor cell responses, parasitic infection, and HIV infection.59-67 IL-10-mediated anergy may be associated with induction of regulatory T cells (Tr1 cells) that produce high levels of IL-10 and can suppress antigen-specific responses in vivo and in vitro.68,69 This effect may not be dependent on soluble mediators but on cell-cell direct interactions. The influence of IL-10 directly on CD4+T cells or indirectly on APC is more important in vivo for the generation ofTr1 cells.

T cell anergy can be induced when naive CD4+ or CD8+ T cells are cultured in the presence of APCs pretreated with IL-10 that downregulate expression of costimulatory molecules.2 In addition, purified T cells activated with anti-CD3 mAbs in the presence of IL-10 also become nonresponsive. Generally, anergy is defined as a long-lasting inability of antigen-specific T cells to proliferate upon rechallenge with antigen-loaded fully competent APCs in two functional assays; proliferation and IL-2 production. The anergic state of IL-10-treated T cells cannot be reversed by the addition of exogenous IL-2 (or IL-15) or stimulation by anti-CD3 mAbs and anti-CD28mAb activities,2,56 indicating that IL-10-anergized cells are not equivalent to those induced by costimulatory blockade. IL-10-anergized T cells acquire regulatory activity and suppress the proliferation of T cells with the same peptide specificity via a cell-cell contact and apparently cytokine-independent mechanism, because IL-10-anergized cells fail to produce cytokines. When IL-10-anergized T cells are forced to proliferate by CD3 mAb crosslinking, they display a profile of cytokine productions, which are distinct from those of classical Th1 or Th2 cells. IL-10-mediated anergy can be associated with induction of a population ofTr1 cells that produce high levels of IL-10 and can suppress antigen-specific responses in vivo and in vitro.30,70,71

Biological Characteristics of Two Types of Regulatory T Cells; IL-10 Producing Tr1 Cells and CD4+CD25+ T Cells

Tr1 cells suppress and regulate immune responses in vitro and in vivo, via the production of IL-10 and TGF-P, in the absence of the T cell growth factors IL-2 and IL-4.69,7 In this intermediate stage, the T cells have already acquired the capacity to suppress T cell responses by suppressive molecules expressed on the cell surface but not through the production of cytokines. Interestingly, human Tr1 cells produce small amounts of IFN-y (whereas murine Tr1 cells do not). Proliferation of Tr1 cells is limited with either polyclonal or antigen-specific TCR activation following the addition of IL-2 or IL-15.73

In the resting state, Tr1 cell clones reveal the same levels ofT cell activation markers as those of normal activated T cells. They constitutively express high levels of IL-2/IL-15RP and Y common chains, as well as a vast repertoire of chemokine receptors.73 Interestingly, Tr1 cells (but not Th1 or Th2 cell clones) express the homing receptor to lymph nodes CCR7.73 Tr1 cells can regulate the responses of naïve and memory T cells in vitro and in vivo as well as suppress both Th1 and Th2 cell-mediated pathology through the production of IL-10 and TGF-P (Fig. 1).72 Mycobacterium-induced production of immunosuppressive cytokines may also contribute to the generation of regulatory T cells that down-regulate immune activation. For example, aerosol treatment of mice with killed Mycobacterium vaccae induces TGF-P-production.74,75 B. pertussis exploits IL-10 to down-regulate the host immune response.1 Bordetella filamentous hemagglutinin (FHA) induces IL-10 production by DC,76 in turn promoting naïve T cells to develop into regulatory cells capable of suppressing IFN-y production by antigen-specific T cells. Thus, bacterial exploitation of host cell capacity to produce immunosuppressive cytokines, particularly IL-10, provides an effective means for invading microbes to modulate host defense mechanisms and evade immune recognition. IL-10 production by bacteria or protozoa infected DC induced regulatory T cells, which have the potential to secrete IL-10.

CD4+CD25+ T cells are distinct from IL-10-producing Tr1 cells. They do not produce IL-10, but can produce TGF-p. CD4+CD25+ T cells are generated in the thymus, and are thought to arise via "altered negative selection" by self-peptides.77,78 The suppressive activity of CD4+CD25+ T cells is related to their ability to inhibit IL-2 production and promote cell cycle arrest in both CD4+ and CD8+ T cells. This requires direct cell-cell contact, and may involve signals through CTLA-4 and/or the glucocorticoid-induced TNF-a receptor. A role for IL-10 in the suppression mediated by these cells is controversial.

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