Peripheral tolerance articles from across Nature Portfolio

In this study, we use a transcriptomic approach as a starting point to explore the heterogeneity of human GATA3-expressing lymphocytes across different tissues and disease contexts. We identify, characterize and functionally validate an abundant progenitor-like memory T cell population with the potential to sustain pathogenic T_H2 cell inflammation.

Studies in mice show that effector T regulatory cells in the gut are most functional in the lamina propria, but this homeostatic niche is disrupted in inflammation, suggesting a spatial mechanism of tolerance to commensal microorganisms.

Increasing evidence suggests that antigen presentation by B cells is critical to the initiation of autoimmunity. Here, the authors demonstrate that tolerance breakdown is initiated outside of germinal centres and that B cells can directly instruct T cells to break tolerance and propagate autoimmune responses.

NBEAL2 loss of function mutations lead to grey platelet syndrome, a condition characterised by α-granule-deficient platelets and, in a proportion of cases, by autoimmunity. Here authors show that NBEAL2 physically interacts with CTLA-4 in human T cells, and NBEAL2 deficiency leads to reduced CTLA-4 surface expression in effector T cells, but not regulatory T cells, thus tipping the balance towards autoimmunity.

Regulatory T cells (T_reg cells) are controlled by a raft of transcription factors besides Forkhead box protein 3 (FOXP3). As detailed in this Review, these accessory transcription factors act alone or together with FOXP3 to coordinate T_reg cell specification and function, and account for heterogeneity of niche-specific T_reg cells.

Exhausted CD8⁺ T cells with diminished effector functions accumulate in tumors. Here, the authors show that hypoxia induces a suppressive phenotype in exhausted T cells and that interfering with hypoxia-mediated CD39 expression limits immunosuppression in the tumor and augments immunotherapy, resulting in arrest of tumor growth.

The blockade of CD28 signalling is known to reduce pathological T cell responses in the context of both autoimmunity and transplantation, but has been associated with impairment of the regulatory T cell compartment. Here the authors show combining costimulation blockade with the administration of interleukin 2 selectively impairs the T effector response whilst maintaining the regulatory T cell pool and suggest functional effect in a murine model of autoimmune diabetes.

In this study, we use a transcriptomic approach as a starting point to explore the heterogeneity of human GATA3-expressing lymphocytes across different tissues and disease contexts. We identify, characterize and functionally validate an abundant progenitor-like memory T cell population with the potential to sustain pathogenic T_H2 cell inflammation.

Interleukin-27 (IL-27) is a pleiotropic cytokine known for its diverse immune regulatory properties. Although innate immune cells are considered the major cellular sources of IL-27, we found that gut regulatory T cells (T_reg cells) secrete IL-27 under inflammatory conditions, allowing them to selectively limit intestinal helper T17 cell (T_H17 cell) responses in various disease settings.

PD-L1 expressed by T cells provides backward and forward signals to restrain both innate and adaptive immune responses in tumor tissues.

The mechanism of action of the lymphocyte checkpoint protein LAG-3 was always rather mysterious. It now seems to operate at least in part by recognizing and suppressing responses to stable complexes of peptide and major histocompatibility complex class II.

Autoimmune diseases are reversed in mice using nanoparticles that display disease-associated antigens bound to MHC class II molecules.