Abstract
Systemic delivery of peptide-major histocompatibility complex (pMHC) class II-based nanomedicines can re-program cognate autoantigen-experienced CD4+ T cells into disease-suppressing T-regulatory type 1 (TR1)-like cells. In turn, these TR1-like cells trigger the formation of complex regulatory cell networks that can effectively suppress organ-specific autoimmunity without impairing normal immunity. In this review, we summarize our current understanding of the transcriptional, phenotypic and functional make up of TR1-like cells as described in the literature. The true identity and direct precursors of these cells remain unclear, in particular whether TR1-like cells comprise a single terminally-differentiated lymphocyte population with distinct transcriptional and epigenetic features, or a collection of phenotypically different subsets sharing key regulatory properties. We propose that detailed transcriptional and epigenetic characterization of homogeneous pools of TR1-like cells will unravel this conundrum.
Highlights
Interleukin 10 (IL-10)-producing regulatory T cells (Tregs) are key to immune homeostasis and play opposing roles in autoimmunity versus cancer
Production of IL-10, coupled to the expression of Latency-Associated Peptide (LAP), Lymphocyte Activation Gene 3 (LAG-3) or chemokine receptor type 5 (CCR5) and Programmed cell death protein 1 (PD-1) in the absence of CD25, or CD4+ cells lacking IL-7 receptor (IL-7R) expression, as well as cells induced by vitamin D3 or CD46-stimulation are some of the examples of cell types identified as TR1 [1, 2]
We have shown that treatment of various mouse models of autoimmune disease with nanoparticles (NPs) coated with disease-relevant peptide-major histocompatibility complex class II molecules [9] suppresses organ inflammation and disease progression without impairing systemic immunity [10,11,12]
Summary
Interleukin 10 (IL-10)-producing regulatory T cells (Tregs) are key to immune homeostasis and play opposing roles in autoimmunity versus cancer. We identify knowledge gaps and propose that detailed transcriptional and epigenetic characterization of homogeneous pools of TR1-like cells will help define both, a true state of FIGURE 1 | Pharmacodynamic activity of pMHCII-NPs. pMHCII-NPs target autoantigen-experienced CD4+ T cells and induce their differentiation into memory TR1-like cells followed by their systemic expansion. This process involves IFN-g and IL-10 signaling, but does not require IL-27.
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