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Whereas most peripheral CD8+αβ T cells highly express CD8αβ heterodimer in healthy individuals, there is an increase of CD8α+βlowor CD8αα αβ T cells in HIV infection or Wiskott-Aldrich syndrome and after bone marrow transplantation. The significance of these uncommon cell populations is not well understood. There has been some question as to whether these subsets and CD8α+βhighcells belong to different ontogenic lineages or whether a fraction of CD8α+βhighcells have down-regulated CD8β chain. Here we assessed clonality of CD8αα and CD8α+βlowαβ T cells as well as their phenotypic and functional characteristics. Deduced from surface antigens, cytotoxic granule constituents, and cytokine production, CD8α+βlowcells are exclusively composed of effector memory cells. CD8αα cells comprise effector memory cells and terminally differentiated CD45RO−CCR7−memory cells. T-cell receptor (TCR) Vβ complementarity-determining region 3 (CDR3) spectratyping analysis and subsequent sequencing of CDR3 cDNA clones revealed polyclonality of CD8α+βhighcells and oligoclonality of CD8α+βlowand CD8αα cells. Importantly, some expanded clones within CD8αα cells were also identified within CD8α+βhighand CD8α+βlowsubpopulations. Furthermore, signal-joint TCR rearrangement excision circles concentration was reduced with the loss of CD8β expression. These results indicated that some specific CD8α+βhighαβ T cells expand clonally, differentiate, and simultaneously down-regulate CD8β chain possibly by an antigen-driven mechanism. Provided that antigenic stimulation directly influences the emergence of CD8αα αβ T cells, these cells, which have been previously regarded as of extrathymic origin, may present new insights into the mechanisms of autoimmune diseases and immunodeficiencies, and also serve as a useful biomarker to evaluate the disease activities.