Stem-like T cells mediate response: Adoptive cell transfer (ACT) is a type of immunotherapy that uses a patient's own T lymphocytes to recognize and attack cancer. ACT has been effective in treating certain patients with metastatic melanoma and is being applied to treat some epithelial cancers. Krishna et al. investigated why some cancer patients respond to ACT, whereas others do not. They identified a population of CD8 ⁺ T cells that had stem-like surface markers that were associated with effective tumor cell killing and favorable response of melanoma patients to ACT. Only a small subset of T cells specific against tumor mutations were found in this stem-like state, whereas most mutation-reactive T cells were terminally differentiated. These findings could be of value in improving cancer immunotherapy outcomes. Science , this issue p. 1328

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4^–CD8^–B220^–TCRαβ⁺ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4⁺ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20⁺CD27^–CD22⁺IgM⁺HLA-DR⁺CXCR5⁺CXCR4⁺⁺CD10⁺CD38⁺ and CD20⁺CD27^–CD22⁺IgM⁺HLA-DR⁺CXCR5⁺CXCR4⁺CD10^–CD38^–) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

Disrupted cytokine networks and autoantibodies play an important role in the pathogenesis of systemic lupus erythematosus. However, conflicting reports and non-reproducibility have hindered progress regarding the translational potential of cytokines in SLE. This study attempts to address the existing knowledge gap using multiplex cytokine assay and machine learning. 67 SLE patients fulfilling SLICC criteria were recruited after informed consent, and circulating cytokines were measured by multiplex cytokine assay kit. We observed a positive association between actual disease activity scores (SLEDAI) and predicted scores from a partial least squares regression (PLSR) analysis of multivariate cytokine response data, with MIP-1α having a strong contribution towards disease activity. Our analysis also highlights increased IL-12 as a potential biomarker in nephritis and elevated MIP-1α as a signature of NPSLE. Using a k-Modes clustering algorithm to stratify patients based on patterns of co-occurrence of circulating autoantibodies, we identified 4 distinct clusters of patients. All 4 clusters had patients with nephritis, but patients in cluster 3 with nephritis were characterised by low levels of housekeeping and homeostatic cytokines and the presence of anti-Ro antibodies, which is a novel observation. Thus, we demonstrate that cytokines can be a surrogate to predict disease activity and organ involvement in SLE. Moreover, we show the utility of unsupervised machine learning algorithms using specific autoantibody signatures to predict renal involvement in SLE.

Heterogeneity in vaccine response, particularly in vulnerable populations like the elderly, represents a significant public health challenge. We conducted an in-depth examination of immune cell profiles before and after SARS-CoV-2 vaccination utilizing mass cytometry in a cohort of healthy Norwegian seniors (65–80 years). We have demonstrated that higher pre-vaccination frequencies of CD27⁺IgD^- class-switched memory B cells and subsets of CD27^-CD24⁺CD38⁺ transitional B cells were associated with a robust vaccine response. Post-vaccination, high responders exhibited increased frequencies of IFN-γ⁺CD4⁺ T cells with antigen recall and a concurrent decrease in CCR6(+) T_H cell subset frequencies compared to low responders. The presence of a γδ T cell subset displaying polyfunctional cytokine responses was also associated with better vaccine response in the elderly. This in-depth profiling sheds light on inherent differences in immune cell frequencies and functions that may offer insights for targeted vaccination strategies in older populations.