Patterns of T‐Cell Phenotypes in Rheumatic Diseases From Single‐Cell Studies of Tissue

Abstract

High‐dimensional analyses of tissue samples from patients with rheumatic diseases are providing increasingly detailed descriptions of the immune cell populations that infiltrate tissues in different rheumatic diseases. Here we review key observations emerging from high‐dimensional analyses of T cells within tissues in different rheumatic diseases, highlighting common themes across diseases as well as distinguishing features. Single‐cell RNA sequencing analyses capture several dimensions of T‐cell states, yet surprisingly, these analyses generally have not demonstrated distinct clusters of paradigmatic T‐cell effector subsets, such as T helper (Th) 1, Th2, and Th17 cells. Rather, global transcriptomics robustly identify both proliferating T cells and regulatory T cells and have also helped to reveal new effector subsets in inflamed tissues, including T peripheral helper cells and granzyme K+ T cells. Further characterization of the T‐cell populations that accumulate within target tissues should enable more precise targeting of biologic therapies and accelerate development of more specific biomarkers to track activity of relevant immune pathways in patients with rheumatic diseases.

T peripheral helper cells in autoimmune diseases*

“…Numerous studies using single-cell RNA-seq and mass cytometry have begun to define "landscapes" of lymphocytes in autoimmune target tissues. [3][4][5][6][7][8] However, abundance does not necessarily imply pathogenicity, as bystander cells may accumulate in large numbers, and compensatory or regulatory cells may also accumulate in inflamed tissues. Applying this approach to blood samples is also reasonable, and may detect circulating T cell phenotypes that are also enriched within tissues 9 ; however, this amplifies the challenge of discriminating the disease-relevant T cells phenotypes from the many innocent circulating T cells that have no role in the disease.…”

“…This approach can be applied to both blood and tissue; however, studies of tissue are more likely to be informative and can demonstrate the prominent T cell phenotypes that accumulate within the inflamed autoimmune target site. Numerous studies using single‐cell RNA‐seq and mass cytometry have begun to define “landscapes” of lymphocytes in autoimmune target tissues 3–8 . However, abundance does not necessarily imply pathogenicity, as bystander cells may accumulate in large numbers, and compensatory or regulatory cells may also accumulate in inflamed tissues.…”

NR4A1-3 nuclear receptor activity and immune cell dysregulation in rheumatic diseases

“…A shared effector phase in IMRDs is the activation of bone marrow-derived macrophages, dendritic cells, poly-morphonuclear neutrophils, and stromal fibroblast cells [including fibroblast-like synoviocytes (FLS)] which are resident cells at sites of inflammation; resulting in aberrant intercellular communication, persistent activation associated with the production of increased amounts of proinflammatory mediators including tumor necrosis factor (TNF) which is considered a pivotal effector cytokine regulating joint pathogenesis (10). Detailed profiling of cell and cytokine signatures in IMRDs indicate that significant differences exist in genetic features, immune-mediated pathogenesis, and treatment responses to targeted therapies (recently reviewed in 1,11,12).…”

“…The principal cells, the cellular components and disease mechanisms which govern the inflammatory pathogenesis of these IMRDs, with an emphasis on the interplay between innate and adaptive immunity (1,11,12), are summarized below:…”

Age-associated CD4 + T cells with B cell–promoting functions are regulated by ZEB2 in autoimmunity

“…For example, CXCR5 − PD-1 hi peripheral helper T (T PH ) cells are involved in the extrafollicular pathway leading to B cell activation (15). The function of T PH cells has been extensively investigated in various autoimmune diseases (16)(17)(18). The main population of B cells that produce autoantibodies in the extrafollicular pathway are likely double-negative 2 (DN2), defined as CD27 − IgD − CXCR5 − CD11c + (13,14).…”