CD28 and CD57 define four populations with distinct phenotypic properties within human CD8⁺ T cells

After repeated antigen exposure, both memory and terminally differentiated cells can be generated within CD8⁺ T cells. Although, during their differentiation, activated CD8⁺ T cells may first lose CD28, and CD28^- cells may eventually express CD57 as a subsequent step, a population of CD28⁺ CD57⁺ (DP) CD8⁺ T cells can be identified in the peripheral blood. How this population is distinct from CD28^- CD57^- (DN) CD8⁺ T cells, and from the better characterized non-activated/early-activated CD28⁺ CD57^- and senescent-like CD28^- CD57⁺ CD8⁺ T cell subsets is currently unknown. Here, RNA expression of the four CD8⁺ T cell subsets isolated from human PBMCs was analyzed using microarrays. DN cells were more similar to "early" highly differentiated cells, with decreased TNF and IFN-γ production, impaired DNA damage response and apoptosis. Conversely, increased apoptosis and expression of cytokines, co-inhibitory, and chemokine receptors were found in DP cells. Higher levels of DP CD8⁺ T cells were observed 7 days after Hepatitis B vaccination, and decreased levels of DP cells were found in rheumatoid arthritis patients. More DP and DN CD8⁺ T cells were present in the bone marrow, in comparison with PBMCs. In summary, our results indicate that DP and DN cells are distinct CD8⁺ T cell subsets displaying defined properties.