Immune memory after vaccination: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has proven highly effective at preventing severe COVID-19. However, the evolution of viral variants, and waning antibody levels over time, raise questions regarding the longevity of vaccine-induced immune protection. Goel et al . examined B and T lymphocyte responses in individuals who received SARS-CoV-2 messenger RNA vaccines. They performed a 6-month longitudinal study of individuals who never had SARS-CoV-2 infection compared with people who had recovered from SARS-CoV-2. Humoral and cellular immune memory was observed in vaccinated individuals, as were functional immune responses against the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) viral variants. Analysis of T cell activity suggested that robust cellular immune memory may prevent hospitalization by limiting the development of severe disease. —PNK

Key differences in both antibody and memory B cell responses to mRNA vaccination were identified on the basis of prior SARS-CoV-2 exposure.

Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. However, characterization of the immunological processes occurring in human pancreatic lymphatic tissues is lacking. Here, we conduct a comprehensive study of immune cells from pancreatic, mesenteric, and splenic lymphatic tissues of non-diabetic control (ND), β cell autoantibody-positive non-diabetic (AAb+), and T1D donors using flow cytometry and CITEseq. Compared to ND pancreas-draining lymph nodes (pLN), AAb+ and T1D donor pLNs display decreased CD4+ Treg and increased stem-like CD8+ T cell signatures, while only T1D donor pLNs exhibit naive T cell and NK cell differentiation. Mesenteric LNs have modulations only in CD4+ Tregs and naive cells, while splenocytes lack these perturbations. Further, T cell expression of activation markers and IL7 receptor correlate with T1D genetic risk. These results demonstrate tissue-restricted immune changes occur before and after T1D onset.

Selective in vivo reprogramming of cytotoxic effector CD8 T (T _eff ) cells holds tremendous promise as a therapeutic tool but has not yet been accomplished. Here, we demonstrate that fractalkine-conjugated mRNA lipid nanoparticles (mRNA-LNPs) can specifically target and deliver mRNA to CX3CR1 ⁺ T _eff cells in vitro and in vivo. In mice, fractalkine-conjugated mRNA-LNPs targeted up to 95% of blood and splenic T _eff cells. In addition, delivery of IL-2–encoding mRNA and human CD62L-encoding mRNA to mouse T _eff cells enabled robust exogenous IL-2 secretion and CD62L expression. In rhesus macaques, fractalkine-conjugated mRNA-LNPs targeted up to ~100% of peripheral blood T _eff cells, and delivery of human CD62L-encoding mRNA enabled cell-surface human CD62L expression on peripheral blood T _eff cells and detection of human CD62L ⁺ T _eff cells in lymphoid tissue. Collectively, these data demonstrate the potential of natural receptor ligand-based targeting of mRNA-LNPs for rapid, efficient, and transient in vivo modification of T _eff cells.

Autoantibodies targeting islet antigen 2 (IA2) are critical diagnostic and prognostic markers for type 1 diabetes (T1D). Standard clinical assays do not differentiate between IgG and IgM isotypes, yet these antibodies have distinct roles in the T1D autoimmunity. We therefore adapted electrochemiluminescence (ECL) assays to separately detect IgG and IgM antibodies against the IA2 intracellular domain (AA601-979). Assay specificity was confirmed by indirect immunofluorescence, which showed autoantibody binding to IA2-overexpressing cells. Plasma samples were analyzed from two independent cohorts: organ donors of the Human Pancreas Analysis Program (HPAP, n = 69) and children from a Janssen–Breakthrough T1D-funded study (n = 65). Diabetics had significantly higher levels of IA2 IgG (p < 0.001) but not IgM (p > 0.05) compared with controls. Notably, IgM and IgG IA2 antibody levels were not correlated. However, IgM modulates IgG detection: IgM depletion increased detected IgG levels to IA2 in some donors, and sera from donors with high IA2-specific IgM levels reduced monoclonal IgG anti-IA2 antibody binding to IA2. Purified IgM from healthy individuals also suppressed monoclonal IgG binding. These findings support distinct, non-redundant roles for IA2-specific IgG and IgM in T1D serology. Isotype-specific autoantibody analysis may improve risk stratification and monitoring of T1D individuals receiving immunomodulatory therapies.