While durable antibody responses from long-lived plasma cell (LLPC) populations are important for protection against pathogens, LLPC may be harmful if they produce antibodies against self-proteins or self-nuclear antigens as occurs in autoimmune diseases such as systemic lupus erythematosus (SLE). Thus, the elimination of autoreactive LLPC may improve the treatment of antibody-driven autoimmune diseases. However, LLPC remain a challenging therapeutic target. Here, we compare the matched bone marrow (BM) and peripheral blood (PBL) plasma cell (PC) compartments of SLE and healthy donors (HD). We show a similar distribution of CD138- and CD138+ PC, including putative LLPC (CD19- CD138+ CD38+), between SLE and HD BM. For both SLE and HD, CD138+ PC are at a higher frequency in BM than PBL. Expression of Ki-67 associates with the PBL compartment where it is found on all PC subsets regardless of CD19 or CD138 expression. Transcriptomic analysis identifies an interferon (IFN) gene signature in transitional B cells in the SLE BM, but surprisingly also in the BM PC derived from SLE. BM PC and B cells phosphorylate STAT1 in response to type I IFN stimulation in vitro, but with decreased fold change compared to those from the PBL. While BM PC bind type I IFN receptor-blocking antibody anifrolumab, it is to a lesser degree than circulating B cells. Anti-nuclear autoantibodies (ANA) are found in the BM supernatant and PBL serum of SLE patients. Both SLE and HD BM-derived PC have increased survival compared to their PBL counterparts when treated with verdinexor. In summary, these findings show evidence of IFN activation in BM PC from SLE.
Copyright © 2025 Alzamareh, Meednu, Nandedkar-Kulkarni, Krenitsky, Barnard, Yasaka, Durrett, Thakar, Rangel-Moreno, Anolik and Barnas.

Long-standing goals of cancer immunotherapy are to activate cytotoxic antitumor T cells across a broad range of affinities while dampening suppressive regulatory T (Treg) cell responses, but current approaches achieve these goals with limited success. Here, we report a de novo IL-21 mimic, 21h10, designed to have augmented stability and high signaling potency in both humans and mice. In multiple animal models and in ex vivo human melanoma patient derived organotypic tumor spheroids (PDOTS), 21h10 showed robust antitumor activity. 21h10 generates significantly prolonged STAT signaling in vivo compared with native IL-21, and has considerably stronger anti-tumor activity. Toxicities associated with systemic administration of 21h10 could be mitigated by TNFα blockade without compromising antitumor efficacy. In the tumor microenvironment, 21h10 induced highly cytotoxic antitumor T cells from clonotypes with a range of affinities for endogenous tumor antigens, robustly expanding low-affinity cytotoxic T cells and driving high expression of interferon-𝛾 (IFN-𝛾) and granzyme B compared to native IL-21, while increasing the frequency of IFN-𝛾 + Th1 cells and reducing that of Foxp3 + Tregs. As 21h10 has full human/mouse cross-reactivity, high stability and potency, and potentiates low-affinity antitumor responses, it has considerable translational potential.

Tumor-associated macrophages (TAMs) are the predominant cells that express programmed cell death ligand 1 (PD-L1) within human tumors in addition to cancer cells, and PD-L1+ TAMs are generally thought to be immunosuppressive within the tumor immune microenvironment (TIME). Using single-cell transcriptomic and spatial multiplex immunofluorescence analyses, we show that PD-L1+ TAMs are mature and immunostimulatory with spatial preference to T cells. In contrast, PD-L1- TAMs are immunosuppressive and spatially co-localize with cancer cells. Either higher density of PD-L1+ TAMs alone or ratio of PD-L1+/PD-L1- TAMs correlate with favorable clinical outcome in two independent cohorts of patients with breast cancer. Mechanistically, we show that PD-L1 is upregulated during the monocyte-to-macrophage maturation and differentiation process and does not require external IFN-γ stimulus. Functionally, PD-L1+ TAMs are more mature/activated and promote CD8+ T cells proliferation and cytotoxic capacity. Together, our findings reveal insights into the immunological significance of PD-L1 within the TIME.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Hunner-type interstitial cystitis (HIC) is a rare, enigmatic inflammatory disease of the urinary bladder with no curative treatments. In this study, we aimed to characterize the unique cellular and immunological factors specifically involved in HIC by comparing with cystitis induced by Mycobacterium bovis bacillus Calmette-Guérin, which presents similar clinicopathological features to HIC. Here, we show that T helper 1/17 +polarized immune responses accompanied by prominent overexpression of interferon (IFN)-γ, enhanced cGAS-STING cytosolic DNA sensing pathway, and increased plasma cell infiltration are the characteristic inflammatory features in HIC bladder. Further, we developed a mouse anti-IFN-γ DNA aptamer and observed that the intravesical instillation of the aptamer significantly ameliorated bladder inflammation, pelvic pain and voiding dysfunction in a recently developed murine HIC model with little migration into the blood. Our study provides the plausible basis for the clinical translation of the anti-IFN-γ DNA aptamer in the treatment of human HIC.
© 2023 The Authors.

Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4+ T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4+ T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4+ T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4+ T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies.
Published by Elsevier Inc.