CD153 promotes B-cell responses to immunization in aged mice

We and others have described homeostatic dysregulation of the CD4+ memory T-cell compartment with age. To gain greater insights into this dysregulation, we performed comprehensive single-cell genomic analysis of endogenous memory CD4+ T cells from young and aged mice. This analysis revealed 16 populations, composed of Th1, Th17, several subsets of regulatory T (Treg) cells, memory T cells, CD4+ CTLs, and T follicular helper (Tfh) cells. One of the most highly expressed genes in aged Tfh cells was Tnfsf8 (CD153 or CD30L), and flow cytometric analysis confirmed age-increased expression of CD153 on endogenous Tfh subsets and memory cells, but not Treg cells. At steady state, the absence of IL-6 significantly reduced CD153 expression on Tfh cells, and pharmacologic inhibition of c-MAF prevented IL-6-driven increase in CD153 expression. After immunization, expression of CD153 on Ag-specific CD4+ Tfh cells persisted significantly longer in aged mice, which required IL-6. Blockade of CD153 significantly reduced Tfh cell expression of ICOS and Ag-specific B-cell responses. Thus, although Tfh-mediated B cell responses, overall, normally decline with age, our data suggest that elevated expression of CD153, driven by an IL-6/c-MAF circuit, potentiates remaining Tfh function in aged mice.