Interleukin 10 regulates cell surface and soluble LIR‐2 (CD85d) expression on dendritic cells resulting in T cell hyporesponsiveness in vitro

Abstract

Dendritic cells (DC) are unique in their ability to stimulate naive T cells to proliferate and to differentiate into effector T cells. DC, however, can also inhibit T cell activation and play a role in central and peripheral tolerance. IL-10 has been shown to render DC tolerogenic by unknown mechanisms. Using a combined monoclonal antibody/retroviral expression cloning approach, we show here that the inhibitory receptor LIR-2 (leukocyte immunoglobulinlike receptor-2, CD85d) is specifically up-regulated by IL-10 on maturing human DC. LPSstimulated, LIR-2-transfected DC inhibited the proliferation of T cells in autologous, as well as allogeneic culture systems in vitro. In addition, overexpression of LIR-2 on resting T cells, which lack LIR-2 expression, inhibited T cell proliferation induced by TCR activation. A novel soluble form of LIR-2 was detected in culture supernatants of maturing DC. IL-10 treatment of DC potently inhibited the production of soluble LIR-2. Recombinant soluble LIR-2 was able to completely restore the proliferation of T cells activated with LPS-plus IL-10-treated DC. Thus, IL-10 renders DC hypostimulatory by up-regulating cell surface LIR-2 and by inhibiting soluble LIR-2 in vitro.

Recombinant Ig-Like Transcript 3-Fc Modulates T Cell Responses via Induction of Th Anergy and Differentiation of CD8+ T Suppressor Cells

“…This effect was suggested to result from competition between membrane ILT4, which is inhibitory, and soluble ILT4 for binding to MHC class I molecules on T cells (17).…”

“…ILT4 binds to HLA class I molecules (14,(17)(18)(19) and its murine homolog was shown to be the paired Ig-like receptor (PIR)-B (20,21). Using an experimental model of chronic antigenic stimulation of recipient rats with UVBirradiated blood from their donor, we demonstrated that CD8 ϩ FOXP3 ϩ Ts cells mediate tolerance to allogeneic heart transplants, inducing PIR-B in donor DC and EC and rendering the graft resistant to rejection (8).…”

“…Treatment of human DC and EC with IL-10 and/or IFN-␣ also induces the up-regulation of ILT3 and ILT4 and renders these cells capable of inhibiting the proliferation of allogeneic T cells (7,11,12,17). The crucial role of ILT3 and ILT4 in the induction of T cell unresponsiveness was documented by overexpressing these receptors in the myelomonocytic cell line KG1.…”

Papel de las células dendríticas tolerogénicas ILT3+/ILT4+ en la respuesta inmunitaria a trasplante de órganos y tejidos

“…A diferencia del sILT4, el sILT3 muestra una fuerte actividad inhibidora (92), lo cual confirma que ILT3 tiene efectos tanto intracelulares como extracelulares, mientras que ILT4 sólo ejerce efectos inhibidores a nivel intracelular, bloqueando la diferenciación de la célula presentadora de antígeno. El sILT3, además, inhibe la "alorreactividad" de las células T CD8+ en células T supresoras antígeno-específicas Foxp3+ y no induce inmunosupresión inespecífica debido a que actúa solamente sobre células T activadas (93).…”

Dendritic Cells Transduced with SOCS1 Gene Exhibit Regulatory DC Properties and Prolong Allograft Survival

“…Therefore, maintaining iDC in an immature steady state is critical for inducing long-term immune tolerance in vivo. Recent studies revealed a certain DC subset with potent immunoregulatory properties in humans and mice, which can be generated by culturing bone marrow-derived dendritic cells (BMDCs) in the presence of inhibitory cytokines such as interleukin (IL)-10 or transforming growth factor (TGF)- (4,5). This DC subset possesses characteristics of a low-expressing mature marker (CD83) and costimulatory molecules that can induce T-cell hyporesponsiveness, promote the generation of regulatory T cells (Tregs), and prolong allograft survival.…”