bims-hummad 2025-08-10 papers

JCI Insight. 2025 Aug 07. pii: e183676. [Epub ahead of print]

BLIMP-1 and CEACAM1 cooperatively regulate human Treg homeostasis and function to control xenogeneic GVHD.

Ying Ding, Aixin Yu, Milos Vujanac, Sabrina N Copsel, Alejandro Moro, Luis Nivelo, Molly Dalzell, Nicolas Tchitchek, Michelle Rosenzwajg, Alejandro V Villarino, Robert B Levy, David Klatzmann, Thomas R Malek.

Regulatory T cells (Tregs) are essential for peripheral tolerance and depend on TCR and IL-2R signaling for their homeostasis and function. In mice, IL-2-dependent BLIMP-1 contributes to Treg homeostasis. BLIMP-1 is a major transcriptional hub in human Tregs, but its mechanisms of action remain undefined. Here, using CRISPR/Cas9 ablation, we show that BLIMP-1 limits human Treg proliferation, but supports IL-10, CTLA4, several immune checkpoints, including CEACAM1, and Treg functional activity. BLIMP-1 restrains Treg expansion to IL-2 by downregulating CD25 and IL-2R signaling, and by enhancing CEACAM1 expression, which in turn inhibits responsiveness to CD3/CD28 signaling and activation of mTOR. Prolonged IL-2R signaling optimizes BLIMP-1 expression, supporting chromosomal opening of CEACAM1 to increased CEACAM1 expression through STAT5- and BLIMP-1-driven enhancers. Correspondingly, CEACAM1 is highly induced on Tregs from autoimmune patients undergoing low-dose IL-2 therapy, and these Tregs showed reduced proliferation. A humanized mouse model of xenogeneic graft versus host disease demonstrates that BLIMP-1 normally promotes, while CEACAM1 restrains, Treg suppressive activity. Collectively, our findings reveal that BLIMP-1 and CEACAM1 function in an IL-2-dependent feedback loop to restrain Treg proliferation and affect suppressive function. CEACAM1 also acts as a highly selective biomarker of IL-2R signaling in human T cells.

Keywords: Adaptive immunity; Autoimmune diseases; Autoimmunity; Immunology; Immunotherapy

DOI: https://doi.org/10.1172/jci.insight.183676

Trends Immunol. 2025 Aug 07. pii: S1471-4906(25)00178-4. [Epub ahead of print]

Advances in human myeloid-engrafting NSG-SGM3 and MISTRG mice.

Hannah Stocks, Jolien Van Cleemput, Linos Vandekerckhove, Andy Wullaert.

Humanized mouse models with transgenic expression of human myelopoiesis-supporting growth factors have enhanced human myeloid cell engraftment and improved the study of human innate immune responses. Here, we discuss the remaining challenges associated with studying innate immunity in humanized NSG-SGM3 and MISTRG mice, as well as potential advances to overcome them.

Keywords: humanized mice; immune engraftment; infection; innate immunity

DOI: https://doi.org/10.1016/j.it.2025.07.011

Nature. 2025 Aug 06.

EBV induces CNS homing of B cells attracting inflammatory T cells.

Epidemiological data have identified Epstein-Barr virus (EBV) infection as the main environmental risk factor for multiple sclerosis, the predominant autoimmune disease of the central nervous system (CNS)1. However, how EBV infection initiates multiple sclerosis pathogenesis remains unclear. Here we demonstrate that EBV expands oligoclonal T-bet+CXCR3+ B cells that home to the CNS in humanized mice. Effector memory CD8+ T cells and CD4+ TH1 cells as well as CD4+ TH17 cells co-migrate to the brain of EBV-infected humanized mice. T-bet+CXCR3+ B cells can colonize submeningeal brain regions in the absence of other lymphocytes and attract T cells. Depletion of B cells with rituximab or blocking of CXCR3 significantly decreases lymphocyte infiltration into the CNS. Thus, we suggest that symptomatic primary EBV infection generates B cell subsets that gain access to the CNS, attract T cells and thereby initiate multiple sclerosis.

DOI: https://doi.org/10.1038/s41586-025-09378-0