Natural Tr1-like cells do not confer long-term tolerogenic memory

Abstract

IL-10-producing Tr1 cells promote tolerance but their contributions to tolerogenic memory are unclear. Using 10BiT mice that carry a Foxp3-eGFP reporter and stably express CD90.1 following IL-10 production, we characterized the spatiotemporal dynamics of Tr1 cells in a house dust mite model of allergic airway inflammation. CD90.1+Foxp3-IL-10+ Tr1 cells arise from memory cells and rejoin the tissue-resident memory T-cell pool after cessation of IL-10 production. Persistent antigenic stimulation is necessary to sustain IL-10 production and Irf1 and Batf expression distinguishes CD90.1+Foxp3-IL-10+ Tr1 cells from CD90.1+Foxp3-IL-10- ‘former’ Tr1. Depletion of Tr1-like cells after primary sensitization exacerbates allergic airway inflammation. However, neither transfer nor depletion of former Tr1 cells influences either Tr1 numbers or the inflammatory response during subsequent allergen memory re-challenge weeks later. Together these data suggest that naturally-arising Tr1 cells do not necessarily give rise to more Tr1 upon allergen re-challenge or contribute to tolerogenic memory. This phenotypic instability may limit efforts to re-establish tolerance by expanding Tr1 in vivo.

Type 1 regulatory T cell-mediated tolerance in health and disease

“…Since Tr1 cells are induced in the periphery (29) and are therefore antigen-experienced, they are thought to be memory CD4 + T cells and behave as such. Evidence to the contrary was introduced in an airway allergy model in which Tr1-like cells substantially reduced airway inflammation in an acute inflammatory setting but showed no role during re-challenge despite being present as resident memory cells (42).…”

“…Since Tr1 cells are induced in the periphery ( 29 ) and are therefore antigen-experienced, they are thought to be memory CD4 + T cells and behave as such. Evidence to the contrary was introduced in an airway allergy model in which Tr1-like cells substantially reduced airway inflammation in an acute inflammatory setting but showed no role during re-challenge despite being present as resident memory cells ( 42 ). The conclusion that Tr1-like cells did not contribute to tolerogenic memory was primarily based on the finding that inflammation was not enhanced in the recall response upon the in vivo depletion of IL-10-producing T cells.…”

Characteristics and sources of tissue-resident memory T cells in psoriasis relapse

“…Rather, Th17 cells are first converted to exTh17 cells during the inflammatory process. Among the surface markers of exTh17, in addition to CD161, CCR6, which maintains Th17, CXCR3 is also expressed [ Jung, S et al, 2023 ; Yadava, K et al, 2019 ]. Although these exTh17 cells no longer secrete IL-17, they still retain some inflammatory properties, such as the production of cytokines including IL-2, TNF, IFN-γ, and GM-CSF [Yadava, K et al, 2019].…”

CAR/Nr1i3 directs T cell adaptation to bile acids in the small intestine

“…9a-c). This suggested that CAR expression and function in Teff cells is increased in response to inflammation, analogous to Tr1 cell dynamics in vivo 28 . Using an orthologous approach to induce intestinal inflammation in wild type or CAR-deficient mice—soluble anti-CD3 injection 23 — we confirmed that CAR was required for anti-CD3 ( i.e ., inflammation)-induced IL-10 upregulation by endogenous effector and regulatory T cell subsets in the siLP, but not the spleen, and was dispensable for steady-state IL-10 expression in T cells from unmanipulated mice (Extended data Figure 9d-f).…”