Autoimmune lymphoproliferative syndrome (ALPS), caused by inherited defects in apoptosis secondary to mutations in genes encoding Fas/CD95/APO-1 and Fas ligand (Fasl)/CD95L, is characterized by nonmalignant lymphadenopathy and splenomegaly, increased T cell receptor α/β+ CD4-CD8- T cells (α/β+ double-negative T cells [α/β+-DNT cells]), autoimmunity, hypergammaglobulinemia, and cytokine abnormalities. The α/β+-DNT cells are immunophenotypically and functionally similar to α/β+-DNT cells that accumulate in lpr and gld mice, which bear genetic mutations in Fas and FasL. In these mice, α/β+-DNT cells express the B-cell-specific CD45R isoform B220. We show that α/β+-DNT cells of ALPS patients, with either Fas or FasL mutations, also express B220. In addition, also similar to LPR/gLD mice, they have an unusual population of B220-positive CD4+ T cells. B220 expression, together with our finding of characteristic lectin binding profiles, demonstrates that cell surface O-linked glycoproteins have undergone specific modifications, which may have consequences for lymphocyte trafficking, cell-cell interactions, and access to alternative apoptosis pathways. © 2001 Academic Press.