Functional analysis of acquired CD28 mutations identified in cutaneous T cell lymphoma

• Published in: Cellular immunology 2017-09, Vol.319, p.28-34
• Main Authors: Gmyrek, Grzegorz B., Pingel, Jeanette, Choi, Jaehyuk, Green, Jonathan M.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; CD28; CD28 Antigens - genetics; CD28 Antigens - immunology; Cell Proliferation; Cell Survival; Costimulation; CTLA-4 Antigen - genetics; CTLA-4 Antigen - immunology; Cutaneous T cell lymphoma; DNA, Complementary - genetics; DNA, Complementary - immunology; Gene Expression; Humans; Lymphocyte Activation; Lymphoma, T-Cell, Cutaneous - genetics; Lymphoma, T-Cell, Cutaneous - immunology; Lymphoma, T-Cell, Cutaneous - pathology; Mice; Mice, Inbred BALB C; Mice, Knockout; Mutant Chimeric Proteins - genetics; Mutant Chimeric Proteins - immunology; Mutation; Primary Cell Culture; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Transfection; Transgenes
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1016/j.cellimm.2017.07.002

•CD28 mutations identified in CTCL increase binding to the ligands for CD28.•These mutations result in increased ligand dependent growth and IL-2 secretion.•Blocking ligand binding may be a novel treatment for some patients with CTCL. CD28 is the major costimulatory receptor on T cells regulating proliferation, survival and effector function. Acquired mutations in the extracellular domain of CD28 have been identified in patients with cutaneous T cell lymphoma, angioimmunoblastic T cell lymphoma and other T cell neoplasms, suggesting it may contribute to disease pathogenesis. We used a heterologous system in which mutant human CD28 was expressed on primary murine T cells deficient in CD28 to ascertain how specific mutations identified in a genetic screen of patients with cutaneous T cell lymphoma affected normal T cell function. All three mutant CD28 proteins examined enhanced CD28-dependent T cell proliferation and effector function. These data suggest that the mutant CD28 isoforms could accelerate tumor cell growth and increase tumor burden in affected patients. Interruption of CD28:ligand interactions may be an effective, targeted therapy for a subset of patients whose tumors bear the mutant CD28 receptor.