Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Oct 18:4:315.
doi: 10.3389/fimmu.2013.00315.

Interleukin 35: a key mediator of suppression and the propagation of infectious tolerance

Brian M Olson  1 , Jeremy A Sullivan, William J Burlingham
Affiliations
Review

Interleukin 35: a key mediator of suppression and the propagation of infectious tolerance

Brian M Olson et al. Front Immunol. .

Abstract

The importance of regulatory T cells (Tregs) in balancing the effector arm of the immune system is well documented, playing a central role in preventing autoimmunity, facilitating graft tolerance following organ transplantation, and having a detrimental impact on the development of anti-tumor immunity. These regulatory responses use a variety of mechanisms to mediate suppression, including soluble factors. While IL-10 and TGF-β are the most commonly studied immunosuppressive cytokines, the recently identified IL-35 has been shown to have potent suppressive function in vitro and in vivo. Furthermore, not only does IL-35 have the ability to directly suppress effector T cell responses, it is also able to expand regulatory responses by propagating infectious tolerance and generating a potent population of IL-35-expressing inducible Tregs. In this review, we summarize research characterizing the structure and function of IL-35, examine its role in disease, and discuss how it can contribute to the induction of a distinct population of inducible Tregs.

Keywords: iTr35; induced regulatory T cells; infectious tolerance; interleukin 35; natural regulatory T cells.

PubMed Disclaimer

Figures

Figure 1
Figure 1
IL-12 family members and signaling pathways. (A) Diagram showing the subunits that form the heterodimeric IL-12 family of cytokines, the subunits that form their receptors, and the predominant STAT molecules that transmit their signals. (B) Diagram showing the potential receptor and signaling pathways utilized by IL-35, which can signal through gp130 or IL-12Rβ2 homodimers, or through a unique gp130:IL-12Rβ2 heterodimer, which results in the formation of a novel STAT1:STAT4 heterodimer that has distinct effects on target cells: maximal suppression, IL-35 expression, and their conversion into iTr35 regulatory T cells.
Figure 2
Figure 2
The effects of natural versus induced PAP-specific CD8+ Tregs pre-immunization, post-immunization, and in long-term follow up. (A) If the observed PAP-specific CD8+CTLA-4+ T cells represent a population of natural Tregs, pre-immunization samples (left panels) have PAP-specific CD8+ nTregs present (red cells) that utilize IL-35 to suppress the activity of PAP-specific effector cells (dark green) both in the periphery (top panels) as well as in the tumor microenvironment (bottom panels), as well as the ability to induce a population of IL-35-expressing Tregs (light green). Administration of a DNA vaccine encoding PAP leads to the presentation of PAP-derived epitopes on the surface of APCs immediately post-immunization (center panels), leading to the expansion of antigen-specific effector cells. However, these cells are in small numbers, and when they traffic to the tumor site, they are outnumbered by PAP-specific nTreg that are able to suppress their proliferation and effector functions. It is not until long-term follow up when these effector responses are able to outnumber antigen-specific nTreg, leading to the generation of productive anti-tumor immunity. (B) In a model where CD8+CTLA-4+ T cells represent a population of novel CD8+ iTr35 cells (light green cells), these iTregs would be able to convert effector cells (dark green) into additional iTreg through their expression of IL-35, thus propagating infectious tolerance to prevent the generation of productive anti-tumor immunity both pre-immunization as well as immediately post-immunization. This process would be predicted to continue until long-term follow up, when antigen-specific effectors could expand to a sufficient level to outnumber these iTreg responses, and potentially prevent the generation of induced antigen-specific Treg by promoting tumor destruction and a non-suppressive tumor microenvironment.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Heusinkveld M, van der Burg SH. Identification and manipulation of tumor associated macrophages in human cancers. J Transl Med (2011) 9:216.10.1186/1479-5876-9-216 - DOI - PMC - PubMed
    1. Nishizuka Y, Sakakura T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science (1969) 166:753–510.1126/science.166.3906.753 - DOI - PubMed
    1. Gershon RK, Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology (1970) 18:723–37 - PMC - PubMed
    1. Gershon RK, Kondo K. Infectious immunological tolerance. Immunology (1971) 21:903–14 - PMC - PubMed
    1. Cantor H, Hugenberger J, Mcvay-Boudreau L, Eardley DD, Kemp J, Shen FW, et al. Immunoregulatory circuits among T-cell sets. Identification of a subpopulation of T-helper cells that induces feedback inhibition. J Exp Med (1978) 148:871–710.1084/jem.148.4.871 - DOI - PMC - PubMed