Influenza vaccination stimulates maturation of the human T follicular helper cell response.

The differentiation and specificity of human CD4+ T follicular helper cells (TFH cells) after influenza vaccination have been poorly defined. Here we profiled blood and draining lymph node (LN) samples from human volunteers for over 2 years after two influenza vaccines were administered 1 year apart to define the evolution of the CD4+ TFH cell response. The first vaccination induced an increase in the frequency of circulating TFH (cTFH) and LN TFH cells at week 1 postvaccination. This increase was transient for cTFH cells, whereas the LN TFH cells further expanded during week 2 and remained elevated in frequency for at least 3 months. We observed several distinct subsets of TFH cells in the LN, including pre-TFH cells, memory TFH cells, germinal center (GC) TFH cells and interleukin-10+ TFH cell subsets beginning at baseline and at all time points postvaccination. The shift toward a GC TFH cell phenotype occurred with faster kinetics after the second vaccine compared to the first vaccine. We identified several influenza-specific TFH cell clonal lineages, including multiple responses targeting internal influenza virus proteins, and found that each TFH cell state was attainable within a clonal lineage. Thus, human TFH cells form a durable and dynamic multitissue network.

CD4+ T cells exhibit distinct transcriptional phenotypes in the lymph nodes and blood following mRNA vaccination in humans.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mRNA vaccination induce robust CD4+ T cell responses. Using single-cell transcriptomics, here, we evaluated CD4+ T cells specific for the SARS-CoV-2 spike protein in the blood and draining lymph nodes (dLNs) of individuals 3 months and 6 months after vaccination with the BNT162b2 mRNA vaccine. We analyzed 1,277 spike-specific CD4+ T cells, including 238 defined using Trex, a deep learning-based reverse epitope mapping method to predict antigen specificity. Human dLN spike-specific CD4+ follicular helper T (TFH) cells exhibited heterogeneous phenotypes, including germinal center CD4+ TFH cells and CD4+IL-10+ TFH cells. Analysis of an independent cohort of SARS-CoV-2-infected individuals 3 months and 6 months after infection found spike-specific CD4+ T cell profiles in blood that were distinct from those detected in blood 3 months and 6 months after BNT162b2 vaccination. Our findings provide an atlas of human spike-specific CD4+ T cell transcriptional phenotypes in the dLNs and blood following SARS-CoV-2 vaccination or infection.

Does Surgical Intervention Alter the Natural History of Degenerative Rotator Cuff Tears? Comparative Analysis from a Prospective Longitudinal Study.

INTRODUCTION: The natural history of rotator cuff tears often involves progressive pain development, tear enlargement, and advancing muscle fatty degeneration. Both surgery and conservative management have proven to be effective treatments. Our study purpose was to compare the short to mid-term effects of rotator cuff repair on shoulder function, progression of tear size, and muscle degeneration compared to controls with asymptomatic tears that developed pain and were managed nonoperatively. METHODS: This comparative study consists of two separate longitudinal study arms. The control group consisted of asymptomatic degenerative cuff tears followed until pain development and then managed nonoperatively with continued surveillance. The surgical group consisted of subjects with degenerative tears that failed nonoperative treatment and underwent surgical intervention with a minimum of 2 years follow-up. Outcomes included VAS pain, ASES, AROM, strength, and ultrasonography. RESULTS: There were 83 controls and 65 surgical shoulders. The surgical group was younger at enrollment (58.9±5.3 yr vs. 61.2±7.8 yr, p=0.04). The median follow-up for control subjects after pain development was 5.1 years (IQR 3.6) and the median postoperative follow-up for the surgical group was 3.0 years (IQR 0.2). Baseline tear widths (median 14 mm, IQR 9 vs. 13 mm, IQR 8; p=0.45) and tear lengths (median 14 mm, IQR 13 vs. median 11 mm, IQR 8; p=0.06) were similar between the surgical group and controls. There were no differences in the baseline prevalence of fatty degeneration of the supraspinatus or infraspinatus muscles between groups (p=0.43 and p=0.58, respectively). At final follow-up, the surgical group demonstrated significantly lower VAS pain (0 [IQR 2] vs. 3.5 [IQR 4], p=0.0002), higher composite ASES (95 [IQR 13] vs. 65.8 [IQR 32], p=0.0002) and ADL scores (29 [IQR 4] vs. 22 [IQR 8], p=0.0002), greater abduction strength (69.6 N [SD 29] vs. 35.9 N [SD 29], p=0.0002), greater active forward elevation (155˚ [SD 8] vs. 142˚ [SD 28], p=0.002), greater active external rotation in abduction (mean 98.5˚, SD 12 vs. mean 78.2˚, SD 20; p=0.0002) compared to controls. Additionally, the prevalence of fatty muscle degeneration was lower in the surgical group for the supraspinatus and infraspinatus (25% vs. 41%, p=0.05; 17% vs. 34%, p=0.03; respectively). CONCLUSION: This prospective longitudinal study comparing a surgical cohort undergoing rotator cuff repair with a control group treated nonoperatively supports the notion that surgical intervention has the potential to alter the early natural history of degenerative rotator cuff disease. Patients in the surgical group demonstrated clinically relevant differences in pain and functional outcomes. Surgical intervention was protective against progressive muscle degeneration compared to nonoperative treatment.

Maturation of germinal center B cells after influenza virus vaccination in humans.

Germinal centers (GC) are microanatomical lymphoid structures where affinity-matured memory B cells and long-lived bone marrow plasma cells are primarily generated. It is unclear how the maturation of B cells within the GC impacts the breadth and durability of B cell responses to influenza vaccination in humans. We used fine needle aspiration of draining lymph nodes to longitudinally track antigen-specific GC B cell responses to seasonal influenza vaccination. Antigen-specific GC B cells persisted for at least 13 wk after vaccination in two out of seven individuals. Monoclonal antibodies (mAbs) derived from persisting GC B cell clones exhibit enhanced binding affinity and breadth to influenza hemagglutinin (HA) antigens compared with related GC clonotypes isolated earlier in the response. Structural studies of early and late GC-derived mAbs from one clonal lineage in complex with H1 and H5 HAs revealed an altered binding footprint. Our study shows that inducing sustained GC reactions after influenza vaccination in humans supports the maturation of responding B cells.