CD153 VACCINE IS A NOVEL SENOTHERAPEUTIC OPTION FOR REMOVING SENESCENCE-ASSOCIATED T CELLS

Abstract

Objective: Senotherapy targeting for senescent cells is designed to attenuate age-related dysfunction and promote healthy aging. Senescence-associated T cells (SA-T cells), defined as CD4+ CD44high CD62Llow PD-1+ CD153+ cells, accumulate in visceral adipose tissues (VAT) in obese individuals. Here, we show the long-lasting effect of using CD153 vaccination to remove SA-T cells from high-fat diet (HFD)-induced obese C57BL/6J mice. Design and method: The peptide vaccines for mouse CD153 consisted of a short peptide sequence conjugated to KLH (keyhole limpet hemocyanin) as a carrier protein to induce the specific CD153 antibody, and knowing the CD153 epitope information allowed five candidate peptide to be selected as antigens. The five peptide vaccines (30 microg of the CD153 peptide per mouse) were conjugated to KLH and coadministered with the Alum adjuvant (Alhydrogel) to seven-week-old male C57BL/6J mice twice at two-week intervals. CD153#D vaccine-induced antibodies effectively recognize the rmCD153 protein, and we selected the CD153#D vaccine as a candidate for further experimental studies. Results: The number of CD153+ SA-T cells increases gradually and systemically with age. Indeed, more CD153+ SA-T cells were observed in the splenic tissues of male C57BL/6J mice at 20 months of age than at 3 months of age (18.7 ± 0.5% vs. 3.8 ± 0.2%; p < 0.0001; n = 3 in each group). In VAT (viceral adipose tissue), CD153+ SA-T cells tended to increase more in elderly mice than in young mice (8.2 ± 1.0% vs. 4.3 ± 1.4%; p = 0.08; n = 3 in each group). We administered a CD153 peptide-KLH conjugate vaccine with Alhydrogel (CD153-Alum) or CpG oligodeoxynucleotide (ODN) 1585 (CD153-CpG) and confirmed an increase in anti-CD153 antibody levels that was sustained for several months. After being fed a HFD for 10–11 weeks, adipose SA-T cell accumulation was significantly reduced in the VAT of CD153-CpG-vaccinated mice, accompanied by glucose tolerance and insulin resistance. A complement-dependent cytotoxicity (CDC) assay indicated that the mouse IgG2 antibody produced in the CD153-CpG-vaccinated mice successfully reduced the number of SA-T cells. Conclusions: These results suggest that the CD153-CpG vaccine might be an optional tool for senolytic therapy.