Aims: Immunoglobulin 4‐related disease (IgG4‐RD) is a multisystem disease, characterised by tumefactive lesions and a swift response to immunosuppressive therapy. Although elevated serum and tissue IgG4 are characteristic, T cells appear to be the primary driver of this immunologically mediated disease. The overarching goal was to examine the role of immunomodulatory cells in IgG4‐RD. Methods and results: Biopsies from patients with IgG4‐RD (n = 39) and mimics of this disease (n = 78) were evaluated for IgG4, IgG, CD8, programmed cell death ligand 1 (PD‐L1) and a subset (n = 18) evaluated for CD4, purine rich box 1 (PU.1), forkhead box protein 3 (FoxP3), PD‐L1, programmed cell death 1 (PD‐1), indoleamine 2,3‐dioxygenase 1 (IDO1) and lymphocyte‐activation gene 3 (LAG3). Data pertaining to demographics and laboratory findings at baseline evaluation was extracted from electronic medical records. When compared to mimics, IgG4‐RD showed increased numbers of PD‐L1‐ (P = 0.0001), PD‐1‐ (P = 0.001), IDO1‐ (P = 0.03), LAG3‐ (P = 0.04) and FoxP3‐ (P = 0.04)‐positive immune cells. The PD‐L1‐positive cells were enriched within aggregates of CD4 and CD8‐positive T cells. Thirty‐one of 39 (80%) IgG4‐RD cases showed greater than five PD‐L1‐positive cells per high‐power field (HPF), while four of 78 (5%) mimics of this disease exceeded this cut‐point. In IgG4‐RD, PD‐L1‐positive macrophages correlated with PD‐1‐ (P = 0.002), LAG3‐ (P = 0.001) and IDO1‐positive cells (P = 0.001); a‐positive correlation was also noted between IgG4/IgG ratio and PD‐L1‐, PD‐1‐ and IDO1‐positive cells. Conclusions: IgG4‐RD shows expansion of mechanisms that maintain peripheral tolerance. The spatial and temporal relationship between T cells and the PD‐L1–PD‐1 axis and the up‐regulation of multiple immunomodulatory proteins suggests that these immunoregulatory mechanisms play a significant role in IgG4‐RD. [ABSTRACT FROM AUTHOR]