A Composite Picture of TcRα/β+ CD4−CD8− T Cells (α/β-DNTCs) in Humans with Autoimmune Lymphoproliferative Syndrome

The discovery of an unusual T-cell subset characterized by the expression of the α/β T-cell receptor without expression of either CD4 or CD8 [α/β-double-negative T cells (α/β-DNTCs)] provided critical insights in the evaluation of a “new” lymphoproliferative disorder known as autoimmune lymphoproliferative syndrome (ALPS). ALPS is a disorder of defective Fas-mediated lymphocyte apoptosis, manifested by accumulation of α/β-DNTCs and other lymphocyte subsets, leading to lymphadenopathy and splenomegaly, autoimmunity, and an increased risk of lymphoma. The expanded population of α/β-DNTCs from ALPS patients has a remarkable uniform phenotype that is for the most part similar to α/β-DNTCs from mice with defective Fas (lpr) or Fas ligand (gld). This is in contrast to the minor α/β-DNTC compartment in healthy individuals that contains multiple, immunophenotypically distinct subpopulations. Current data indicate that α/β-DNTCs from ALPS patients are derived from cytotoxic CD8+ T cells, chronically activated in vivo but anergic in vitro. Their anergic state may be related to persistent modifications of O-linked carbohydrates on cell surface molecules, such as CD43 and CD45, as well as to the increased presence of interleukin-10. Although largely consistent with a model of (linear) CD8+ cytotoxic T-cell differentiation, the expression patterns of certain surface molecules, such as CD27 and CD28, are not consistent with this model. This may be the result of the perturbed homeostasis of lymphocytes in ALPS, thereby revealing pathways of differentiation and immunophenotypes, including phenotypes pertaining to cell surface glycosylation that are hidden from view in healthy individuals.