Allospecific splenic Tr1 cells drive effector T cell exhaustion through up-regulated Areg-EGFR signaling to promote transplant tolerance
Year: 2026
Type: article
Abstract: Inducing stable tolerance to transplants remains a challenge in immunology. Previously, we induced tolerance to allogeneic islets in nonhuman primates by preemptive alloantigen delivery to antigen-presenting cells in situ. Here, mass cytometry phenotyping with incorporated donor-derived MHC-I peptide–loaded MHC-II tetramers revealed accumulation of allospecific CD4 + T cell clusters in the spleen of tolerant recipients. Areg + Tr1 regulatory and terminally exhausted EGFR hi T (Tex) cells represented the predominant allospecific subsets. Trajectory analysis showed that antigen-experienced effector memory T cells differentiated into suppressive Areg + Tr1 and EGFR + TOX + Nur77 + TCF-1 − Tex subsets. Cell-cell communication mapping showed that exhausted and effector memory T cells engaged with allospecific Tr1 cells via the Areg-EGFR axis. Gene silencing studies confirmed that Tr1 cells use Areg-EGFR signaling to drive the metabolic suppression and epigenetic reprogramming of CD4 + T cells through a Nur77-dependent pathway. These findings point to the splenic Areg + Tr1 cell-EGFR + Teff cell axis as a critical immunoregulatory pathway in peripheral transplant tolerance.
Source: Science Advances
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
Awards: G1919376332, Deep Immune Profiling of Nonchimeric Tolerance of Transplants in Nonhuman Primates, CTSA Postdoctoral T32 at University of Minnesota, G816098755, University of Minnesota Clinical and Translational Science Institute (UMN CTSI), The role of the spleen in maintaining immune tolerance to transplanted islets
OpenAlex ID: W7119085886