Infectious Tolerance as Seen With 2020 Vision: The Role of IL-35 and Extracellular Vesicles

Abstract

Originally identified as lymphocyte regulation of fellow lymphocytes, our understanding of infectious tolerance has undergone significant evolutions in understanding since being proposed in the early 1970s by Gershon and Kondo and expanded upon by Herman Waldman two decades later. The evolution of our understanding of infectious tolerance has coincided with significant cellular and humoral discoveries. The early studies leading to the isolation and identification of Regulatory T cells (Tregs) and cytokines including TGFβ and IL-10 in the control of peripheral tolerance was a paradigm shift in our understanding of infectious tolerance. More recently, another potential, paradigm shift in our understanding of the "infectious" aspect of infectious tolerance was proposed, identifying extracellular vesicles (EVs) as a mechanism for propagating infectious tolerance. In this review, we will outline the history of infectious tolerance, focusing on a potential EV mechanism for infectious tolerance and a novel, EV-associated form for the cytokine IL-35, ideally suited to the task of propagating tolerance by "infecting" other lymphocytes.

Keywords: IL-35; exosomes; extracellular vesicle; immunotherapy; infectious tolerance.

Figure 1

Model for EV-Associated Dendritic Cell “split” tolerance. An extracellular vesicle (EV) derived from maternal micro-chimerism [or from certain allograft types] is taken up by a host dendritic cell (blue). These EV contain microRNA and express surface membrane-bound allo-MHC class I (green) and II (olive), along with the co-stimulatory molecule CD86. After uptake, the microRNA escape to the endoplasmic reticulum where they guide production of PD-L1 (purple). The allo-class I and class II are either (bottom) preserved intact and re-distributed as components of acquired membrane domains (dashed red lines) containing CD86, or (top) broken down in lysosomal vesicles to peptides that are loaded onto “self” MHC class II. These 2 forms of allo-antigen presentation, semi-direct (lower left and right), and indirect (upper left and right) are kept separate by the host DC, allowing positive co-stimulation of semi-direct pathway, allo-specific host CD4 and CD8 T cells via CD86-CD28 (pink) interaction. Yet even as these productive interactions are occurring, the CD4 T helper cells are being strongly inhibited by PD1 (yellow) interaction with the negative co-stimulator PD-L1. The net result is limited acute rejection in the short term, followed by long-term protection of the allograft from chronic rejection (“split” tolerance).

Figure 2

Model for IL-35⁺ EV-Associated Infectious Tolerance from Tregs in Transplantation. Treg cells (red) produce IL-35⁺ EVs in response to antigenic stimulation. IL-35⁺ EVs are bound by lymphoid cells at their IL-35 receptor leading to primary suppression. The primary suppression by IL-35⁺ EVs of conventional CD4 T cells causes some to express Foxp3, becoming inducible Tregs (iTregs-blue) that produce IL35⁺ EVs, while others become non-Foxp3⁺ IL-35⁺ EV producers (iTr35-purple); IL-35⁺ EVs can also induce Bregs (green) to produce their own IL-35⁺ EVs. Secondary suppression by IL35⁺ EV acquiring cells leads to an exponential increase in the cytokine's impact. This can occur through both an increase in inhibitory receptor expression, including PD-1, LAG3, and TIM3, in addition to bystander suppression of local T cell function.