Human T-cell receptor (TCR) α/β⁺ CD4^-CD8^- T cells express oligoclonal TCRs, share junctional motifs across TCR V_β-gene families, and phenotypically resemble memory T cells

Most human T cells express the TCR α/β and either CD4 or CD8 molecules (single positive, SP); however, small numbers lack CD4 and CD8. In inbred mice, α/β CD4^-CD8^- (double negative, DN) T cells preferentially express certain β variable region (V_β) families and may arise via unique developmental pathways. Increased percentages of α/β DN T cells have been identified in some human and murine autoimmune and immunodeficiency diseases. However, their contribution to disease pathology or normal immunity is unknown. To study the cell surface phenotype and TCR diversity of human α/β DN T cells, these cells were isolated from the peripheral blood of healthy adults. The proportion of α/β DN T cells expressing molecules associated with activation (HLA-DR), previous exposure to antigen (CD45RO), and cytotoxic function (CD56, CD57, and CD11b) was increased relative to SP T cells. The TCR V_β repertoire of α/β DN T cells was different from that of α/β SP T cells, although most major gene families were present. For example, higher proportions of V_β11, a minor gene family in peripheral blood leukocytes, were found in most α/β DN T-cell samples. In contrast to mice, no dominant V_β family was used consistently in different human individuals. Within an individual α/β DN T cells possessed an oligoclonal TCRβ repertoire with conservation of several distinct junctional amino acid motifs with one joined to three different V_β genes in two individuals, suggesting that these cells have undergone a selection process driven by a limited set of ligands. The possibility that they may represent, at least in part, originally SP T cells anergized by down-modulation of CD4 or CD8 must also be entertained. Overall, this study demonstrates that human peripheral blood α/β DN T cells possess unique phenotypic and TCRβ repertoire characteristics when compared with the major α/β SP T cell populations and thus may serve specialized immunologic functions and/or have an unusual origin.