CD153 expression in aged Tfh cells sustains B-cell responses to immunization via IL-6/c-MAF circuit

Aging is associated with immunosenescence, a decline in immune function that compromises vaccine efficacy and increases susceptibility to infections. A key aspect of this decline is the dysregulation of the CD4+ memory T-cell compartment, particularly T follicular helper (Tfh) cells, which are crucial for effective B-cell responses and antibody production. While overall Tfh-mediated B-cell responses diminish with age, the mechanisms by which some residual function is maintained or even potentiated in the aged immune system remain poorly understood. Understanding these compensatory pathways could reveal novel targets for boosting immunity in the elderly.

Researchers performed comprehensive single-cell genomic analysis of endogenous memory CD4+ T cells from young and aged mice to identify age-related changes. This was followed by flow cytometric analysis to confirm protein expression. They investigated the role of IL-6 and c-MAF in regulating CD153 expression using genetic absence of IL-6 and pharmacologic inhibition of c-MAF. Mice were immunized, and the persistence of CD153 on Ag-specific CD4+ Tfh cells was tracked. Finally, CD153 was blocked to assess its impact on ICOS expression and Ag-specific B-cell responses.

Single-cell genomic analysis revealed 16 distinct CD4+ T-cell populations, including Th1, Th17, Treg, CD4+ CTLs, and Tfh cells. Tnfsf8 (encoding CD153) was among the most highly expressed genes in aged Tfh cells, confirmed by flow cytometry showing age-increased CD153 expression on Tfh subsets and memory cells. At steady state, the absence of IL-6 significantly reduced CD153 expression on Tfh cells, and pharmacologic inhibition of c-MAF prevented the IL-6-driven increase in CD153. After immunization, CD153 expression on Ag-specific CD4+ Tfh cells persisted significantly longer in aged mice, a process that required IL-6.