A role for Tregsand their secreted cytokines, interleukin-10(IL-10), and transforming growth factor beta (TGF-β), in T cell exhaustion in tumors and viral infections has been suggested. However, it remains unclear whether Tregs can directly promote exhaustion of antigen-specific T cells. Reversal of CD8+ T cell exhaustionand efficient control of viral load was noted following dual blockade of Tregs and PDL1 or IL-10 and PDL1.
Tregs suppress effector cells by numerous mechanisms, one of which is secretion of inhibitory cytokines. One such inhibitory cytokine is IL-35.
Interleukin-35 belongs to the IL-12 family of cytokines. It is a dimeric protein composed of two subunits – p35 and EBI3, which are shared with other IL-12 family members, specifically IL-12 and IL-27.
Interleukin-35 is secreted by regulatory T-cells (Tregs) and exerts immunosuppressive effectsmostly through an inhibition of T cell proliferation and function.
In the Immunity study Meghan Turnis and colleagues from the Departments of Immunology at the University of Pittsburgh and the St. Jude Children’s Research Hospital, Memphis, TN tested the hypothesis that interleukin-35 produced by Tregs contributes substantially to the suppressive tumor milieu and that depletion will enhance tumor-specific immunity.
The authors demonstrate that the tumor microenvironment is characterized by a substantial enrichment of IL-35+ Treg cells.
According to the authors their results suggest that Treg cells are the major, and perhaps, the only source of interleukin-35 in the tumor microenvironment.
Importantly, the study indicates that the tumor-associated interleukin-35 contributes to reduced antigen-specific T cell infiltration, decreased effector immune function and memory, and increased tumor burden.
This is achieved mostly by the T-cell exhaustion in tumors, driven by interleukin-35, as the result of the increased expression of several inhibitory receptors such as PD1, TIM3 and LAG3.
The authors argue that their results may reveal an important and previously unrecognized mechanism for immune evasion – namely, the inflammatory milieu-mediated enrichment of IL-35+ Treg population within the tumor microenvironment.
According to the authors, it is highly likely that IL-35 is more prominently utilized as suppressive mechanism in cancer than in any other inflammatory or autoimmune disease or condition.