No abstract

CD4 T cells help CD8 T cells differentiate into competent effector and memory cells. We recently showed that CD4 T cells are essential for CD8 T cell differentiation into brain-resident memory (bTRM) during polyomavirus (PyV) infection. Here we identify IL-21 as the CD4 T cell help. Using MHC-II tetramers for two epitopes in mouse PyV, we show brain PyV-specific CD4 T cells express PD-1 and CXCR5. IL21-VFP reporter mice revealed CD4 T cells as the only cellular source of IL-21 in the brain. 2D micropipette adhesion assays, measuring TCR affinity, showed brain IL-21-producing CD4s have higher affinity TCRs than IL-21− cells. RNAseq analysis of IL-21+ vs. IL-21− brain CD4s corroborates that IL-21 production is positively associated with TCR affinity and that IL-21 producers are positively enriched for TFH signature genes. We further found that IL-21 receptor (IL21R) is required for CD8 TRM differentiation. Brain CD8 T cells upregulated IL21R at 15 days post-infection, coincident with expression of the TRM marker CD103. Few CD8 T cells in brains of IL-21R−/− mice expressed CD103, a finding confirmed using donor anti-PyV CD8 T cells lacking IL-21R in infected wild type (WT) recipients. Unlike IL21R-sufficient CD8s, IL21R−/− CD8 T cells are not maintained in the brain upon systemic CD8 antibody depletion. IL21R−/− CD8s also have a diminished response to a rechallenge in the brain than what we observed with WT CD8 T cells. RNAseq analysis revealed IL21R−/− CD8 T cells were negatively enriched for TRM core signature genes and oxidative metabolism genes compared to IL-21R-sufficient CD8 T cells. Thus, we conclude that IL-21 produced by high-affinity, PyV-specific CD4 T cells in the brain is required for differentiation of CD8 bTRM during PyV CNS infection.

Background Older adults with myeloid malignancies are susceptible to treatment-related toxicities. Accelerated DNAm age, or the difference between DNA methylation (DNAm) age and chronological age, may be used as a biomarker of biological age to predict individuals at risk. In addition, cancer treatment can also lead to accelerated DNAm age. Exercise is a promising intervention to reduce or prevent functional, psychological, and cognitive impairments in older patients with myeloid malignancies, yet there is little evidence of the effects of exercise on DNAm age. We explored (1) the associations of accelerated DNAm age with physical, psychological, and cognitive functions at baseline; (2) changes in DNAm age from baseline to post-intervention; and (3) the associations of changes in accelerated DNAm age with changes in functions from baseline to post-intervention. Methods We enrolled older patients with myeloid malignancies to a single-arm pilot study testing a mobile health (mHealth) exercise intervention that combines an exercise program (EXCAP©®) with a mobile application over 2 cycles of chemotherapy (8–12 weeks). Patients completed measures of physical, psychological, and cognitive functions and provided blood samples for analyses of DNAm age at baseline and post-intervention. Paired t-tests or Wilcoxon signed rank tests assessed changes in DNAm ages, and Spearman’s correlation assessed the relationships between accelerated ages and functions. Results We included 20 patients (mean age: 72 years, range 62–80). Accelerated GrimAge, accelerated PhenoAge, and DunedinPACE were stable from baseline to post-intervention. At baseline, DunedinPACE was correlated with worse grip strength (r = -0.41, p = 0.08). From baseline to post-intervention, decreases in accelerated GrimAge (r = -0.50, p = 0.02), accelerated PhenoAge (r = − 0.39, p = 0.09), and DunedinPace (r = − 0.43, p = 0.06) were correlated with increases in distance walked on 6-min walk test. Decreases in accelerated GrimAge (r = − 0.49, p = 0.03), accelerated PhenoAge (r = − 0.40, p = 0.08), and DunedinPace (r = − 0.41, p = 0.07) were correlated with increases in in grip strength. Conclusions Among older adults with myeloid malignancies receiving chemotherapy, GrimAge and PhenoAge on average are stable after a mHealth exercise intervention. Decreases in accelerated GrimAge, accelerated PhenoAge, and DunedinPACE over 8–12 weeks of exercise were correlated with increased physical performance. Future trials assessing the effects of exercise on treatment-related toxicities should evaluate DNAm age. Trial registration Clinicaltrials.gov identifier: NCT04981821.