T-cell dynamics after high-dose chemotherapy in adults: Elucidation of the elusive CD8+ subset reveals multiple homeostatic T-cell compartments with distinct implications for immune competence

Recovery of total T cell numbers after in vivo T-cell depletion in humans is accompanied by complex perturbation within the CD8⁺ subset. We aimed to elucidate the reconstitution of CD8⁺ T cells by separate analysis of putative naïve CD95^- CD28⁺, memory CD95⁺ CD28⁺ and CD28^- T cell compartments after acute maximal depletion by high-dose chemotherapy (HD-ChT) in women with high-risk breast cancer. We found that recovery of putative naïve CD8⁺ CD95^- CD28⁺ and CD4⁺ CD95^- CD28⁺ T cells, was compatible with a thymus-dependent regenerative pathway since their recovery was slow and time-dependent, their values were tightly related to each other, and their reconstitution patterns were inversely related to age. By analysing non-naïve T cells, a striking diversion between putative memory T cells and CD28^- T cells was found. These latter increased early well beyond normal values, thus playing a pivotal role in total T-cell homeostasis, and contributed to reduce the CD4:CD8 ratio. In contrast, putative memory T cells returned to values not significantly different from those seen in patients at diagnosis, indicating that this compartment may recover after HD-ChT. At 3-5 years after treatment, naïve T cells persisted at low levels, with expansion of CD28^- T cells, suggesting that such alterations may extend further. These findings indicate that CD28^- T cells were responsible for 'blind' T-cell homeostasis, but support the notion that memory and naïve T cells are regulated separately. Given their distinct dynamics, quantitative evaluation of T-cell pools in patients undergoing chemotherapy should take into account separate analysis of naïve, memory and CD28^- T cells.