PD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation

Abstract

Chronic inflammatory diseases are characterized by recurrent inflammatory attacks in the tissues mediated by autoreactive T cells. Identity and functional programming of CD8+ T cells at the target site of inflammation still remain elusive. One key question is whether, in these antigen-rich environments, chronic stimulation leads to CD8+ T cell exhaustion comparable to what is observed in infectious disease contexts. In the synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients, a model of chronic inflammation, an overrepresentation of PD-1+CD8+ T cells was found. Gene expression profiling, gene set enrichment analysis, functional studies, and extracellular flux analysis identified PD-1+CD8+ T cells as metabolically active effectors, with no sign of exhaustion. Furthermore, PD-1+CD8+ T cells were enriched for a tissue-resident memory (Trm) cell transcriptional profile and demonstrated increased clonal expansion compared with the PD-1- counterpart, suggesting antigen-driven expansion of locally adapted cells. Interestingly, this subset was also found increased in target tissues in other human chronic inflammatory diseases. These data indicate that local chronic inflammation drives the induction and expansion of CD8+ T cells endowed with potential detrimental properties. Together, these findings lay the basis for investigation of PD-1-expressing CD8+ T cell targeting strategies in human chronic inflammatory diseases.

Polyfunctional, Proinflammatory, Tissue‐Resident Memory Phenotype and Function of Synovial Interleukin‐17A+CD8+ T Cells in Psoriatic Arthritis

“…Trm cells are rapidly emerging as potential contributors to inflammation in several immune‐mediated inflammatory diseases . To our knowledge, this is the first study to show that Tc17 cells form part of the synovial Trm pool, and only the second description of Trm‐like cells in the context of human immune‐mediated arthritis . Our data also show that a high proportion of synovial Tc17 cells express markers typically associated with homing to the skin or gut.…”

“…To date, the majority of studies have focused on identifying IL‐17A–producing CD4+ T (Th17) cells or group 3 innate lymphoid cells in the inflamed joints of patients with PsA/SpA, yet the strong association of major histocompatibility complex (MHC) class I and other CD8+ T cell/MHC class I–related loci ( RUNX3, ERAP1/2 ) suggests that CD8+ T cells play an important role in PsA/SpA . We previously demonstrated the enrichment of IL‐17A–expressing CD8+ T (Tc17) cells in the synovial fluid (SF) of patients with PsA ; Tc17 cells have also been observed in the SF of patients with juvenile idiopathic arthritis (JIA) and at the site of inflammation in other immune‐mediated inflammatory diseases (for review, see refs. and ).…”

“… and ). In humans, Trm cells have been observed in skin, lung, gut, and brain tissue, and a recent study demonstrated the presence of CD8+ T cells with a tissue‐resident memory phenotype in the SF of patients with JIA . As such, Trm cells are hypothesized to contribute to the immunopathogenesis of human immune‐mediated inflammatory disease.…”

Antigen-driven PD-1+TOX+EOMES+ and PD-1+TOX+BHLHE40+ synovial T lymphocytes regulate chronic inflammation in situ

“… Introduction/Abstract T lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro-inflammatory cytokines upon re-stimulation in vitro 1–29 . Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA) 30–33 .…”

Contrasting inflammatory signatures in peripheral blood and bronchoalveolar cells reveal compartment-specific effects of HIV infection

“…PD-1 expression in CD8 + T cells has been associated with exhaustion 19 . However, in juvenile idiopathic arthritis, PD-1 + CD8 + T cells derived from synovial fluid were metabolically active functional effector memory T cells, suggesting that PD-1 expression could also act as a marker of locally adapted functional T cells 20 . Thus, depending on context, PD-1 could be a marker of either exhaustion or local activation in tissues.…”