A molecular basis for T cell suppression by IL‐10: CD28‐associated IL‐10 receptor inhibits CD28 tyrosine phosphorylation and phosphatidylinositol 3‐kinase binding

Abstract

Specific immune suppression and induction of anergy in T cells are essential processes in regulation and circumvention of immune defense. IL‐10, a suppressor cytokine of T cell proliferative and cytokine responses, plays a key regulatory role in tolerizing exogenous antigens during specific immunotherapy and natural exposure. The present study demonstrates that IL‐10 induces T cell suppression by blocking the CD28 costimulatory signal. T cell receptor counting and T cell proliferation studies by anti‐CD3 and anti‐CD28 stimulation in the presence or absence of IL‐10 revealed that IL‐10 only inhibits T cells stimulated by low numbers of triggered T cell receptors and that depend on CD28 costimulation. T cells receiving a strong signal by the T cell receptor alone and that do not require CD28 costimulation are therefore not affected by IL‐10. Coprecipitation experiments demonstrated that CD28 and the IL‐10 receptor are associated in activated T cells. IL‐10 inhibited CD28 tyrosine phosphorylation, the initial step of the CD28 signaling pathway. In consequence, phosphatidylinositol 3‐kinase p85 binding to CD28 was inhibited. Thus, IL‐10‐induced selective inhibition of the CD28 costimulatory pathway demonstrates a decisive mechanism in determining whether a T cell will contribute to an immune response or become anergic.

Nickel-induced IL-10 down-regulates Th1- but not Th2-type cytokine responses to the contact allergen nickel

“…IL-10 is thought to exert its effects by down-regulating the expression of costimulatory molecules required for appropriate antigen presentation [34,35]. At the molecular level, IL-10 has been shown to mediate direct T cell suppression by inhibiting CD28 tyrosine phosphorylation and phosphatidylinositol 3-kinase binding upon interaction with a CD28-associated IL-10 receptor [31,36]. De la Barrera et al [35] demonstrated that neutralization of endogenous IL-10 induced strong CD4 + and CD8 + T cell-mediated lytic activity which correlated with an increased expression of costimulatory molecules on target cells from patients infected with Mycobacterium tuberculosis.…”

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

“…IL-10 can also inhibit the release of IFN-γ and IL-2 and thus inhibit T cell growth [50]. This immunosuppressive effect of IL-10 is mediated by blocking the CD28 and ICOS costimulatory signaling [51,52].…”

Regulation of T cells and cytokines by the interleukin‐10 (IL‐10)‐family cytokines IL‐19, IL‐20, IL‐22, IL‐24 andIL‐26

“…It has been shown to activate B cells for immunoglobulin production, induce proliferation of mast cells and increase NK cell cytotoxicity [5][6][7]. IL-10 can also inhibit CD4 + T cell chemotaxis towards IL-8 [1,8] and T cell apoptosis [9] by leading to Bcl-2 up-regulation. Interestingly, it can induce the proliferation of CD8 + T cells [10].…”