Cytomegalovirus infection reduced CD70 expression, signaling and expansion of viral specific memory CD8⁺ T cells in healthy human adults

Background: Cytomegalovirus (CMV) infection leads to effector memory CD8⁺ T cell expansion and is associated with immune dysfunction in older adults. However, the molecular alterations of CMV-specific CD8⁺ T cells in CMV infected healthy young and middle-aged adults has not been fully characterized. Results: We compared CD8⁺ T cells specific for a CMV epitope (pp65_495-503, NLV) and an influenza A virus (IAV) epitope (M1_58-66, GIL) from the same young and middle-aged healthy adults with serum positive for anti-CMV IgG. Compared to the IAV-specific CD8⁺ T cells, CMV-specific CD8⁺ T cells contained more differentiated effector memory (T_EM and T_EMRA) cells. Isolated CMV-specific central memory (T_CM) but not naïve (T_N) cells had a significant reduced activation-induced expansion in vitro compared to their IAV-specific counterparts. Furthermore, we found that CD70 expression was reduced in CMV-specific CD28⁺CD8⁺ T_CM and that CD70⁺ T_CM had better expansion in vitro than did CD70^- T_CM. Mechanistically, we showed that CD70 directly enhanced MAPK phosphorylation and CMV-specific CD8⁺ T_CM cells had a reduced MAPK signaling upon activation. Lastly, we showed that age did not exacerbate reduced CD70 expression in CMV- specific CD8⁺ T_CM cells. Conclusion: Our findings showed that CMV infection causes mild expansion of CMV-NLV-specific CD8⁺ T cells, reduced CD70 expression and signaling, and proliferation of CMV-NLV-specific CD8⁺ T_CM cells in young and middle-aged healthy adults and revealed an age-independent and CMV infection-specific impact on CD8⁺ memory T cells.