Transcriptional and epigenetic re-programming of autoantigen-specific cd4+ t cells by pmhc class ii-based nanomedicines
- Autores: Patricia Solé Sánchez
- Directores de la Tesis: Pere Santamaria Vilanova (dir. tes.), Pau Serra (codir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2020
- Idioma: español
- Tribunal Calificador de la Tesis: Jorge Ferrer Marrades (presid.), Luis F. Santamaría Babi (secret.), Peter van Endert (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
- Materias:
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- Resumen
Regulatory cells are essential to immune homeostasis. Both autoimmune diseases and the progression of cancer are related to alterations in the development and/or function of the regulatory compartment. In addition to the well-known FoxP3+ T regulatory (Treg) cells, other FoxP3- IL-10-producing subsets have been described. These are generally referred to as T-regulatory type 1 cells (Tr1) although they appear to comprise a phenotypically heterogeneous subset. Cells negative for CD25 and expressing LAP, LAG-3 or CCR5 and PD-1, cells IL-7R negative or regulatory cells induced by vitamin D3 or CD46-stimulation are some examples of cell types that may correspond to cells of a single lineage but were identified as distinct based on incomplete market sets. Although CD49b and LAG-3 co-expression have been associated with IL-10 expression in both murine and human Tr1-like cells, some of the above Tr1-like subsets were Lag-3low, and both markers lack the specificity and sensitivity required to address this conundrum. Other surface markers have been associated with the Tr1 phenotype, including ICOS, CTLA-4, PD-1, TIM-3 or Tigit, as well as transcription factors like T-bet, AhR and/or Nfil3, among others.
The lack of Tr1 subset-specific markers for cell isolation and downstream phenotypic, functional, transcriptional and epigenetic studies, has hindered the study of this T cell subset, specifically whether all these IL-10-producing T-reg cells that do not belong to the classical FoxP3+/CD25+ subset actually belong to one or a collection of phenotypically and transcriptionally different subsets of cells. In fact, a number of studies employing a variety of therapeutic approaches for the treatment of autoimmunity have claimed the Treg-ness/Tr1-ness of the pharmacodynamic response, often solely on the basis of increased IL-10 expression in bulk splenic CD4+ T-cells. Thus, it is unclear if the various phenotypes ascribed to IL-10-producing FoxP3-negative CD4+ T-cells correspond to non-Tr1 cell types, to different stages of Tr1 cell differentiation along a continuum, or to a bona-fide subset of terminally-differentiated Tr1 cells with distinct phenotypic and/or functional properties and either stable or plastic gene expression programs. Unfortunately, the transcriptional and epigenetic correlates that help define true Tr1-likeness remain undefined.
Treatment with nanoparticles (NPs) coated with mono-specific disease-relevant peptide-major histocompatibility complex class II (pMHCII) molecules suppresses inflammation in several organ-specific autoimmune disease models without impairing systemic immunity. We have provided evidence of therapeutic efficacy in animal models with established type 1 diabetes (T1D), experimental autoimmune encephalomyelitis (EAE), experimental arthritis, and more recently, spontaneous primary biliary cholangitis (PBC), primary sclerosis cholangitis (PSC) and autoimmune hepatitis (AIH). pMHCII-NP therapy functions by reprogramming cognate antigen-experienced CD4+ T cells into FoxP3- IL-10-7-independent manner.
