LAUSR

T-cell-specific surface glycoprotein CD28 belongs to the subfamily of costimulatory molecules characterized by an extracellular immunoglobulin variable-like domain. Other members of the subfamily include inducible T-cell costimulator (ICOS), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), programmed cell death-1 (PD1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and others. Na€ıve T cells are activated by two signals. The first involves antigenspecific T-cell receptor (TCR) signalling, and the second is antigen-non-specific and requires signalling through costimulatory receptors, of which the best characterized is the interaction of CD28 on T cells with CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells. CD28 is expressed constitutively on both resting and activated T cells, whereas the expression of other members of the family, ICOS and CTLA4, is induced by TCR stimulation. CTLA4 has a higher affinity for CD80 and CD86 receptors than CD28, and when CTLA4 is expressed on T cells predominantly, CD80 and CD86 are occupied by CTLA4, and CD28 cannot bind to CD80 and CD86 and T-cell activation is suppressed. The cytoplasmic region of CD28 contains two main signalling motifs, the membrane-proximal YMNM motif and two proline-rich motifs. When CD28 binds to its ligands, protein tyrosine kinases are recruited to the CD28 cytoplasmic tail and they phosphorylate CD28, which in turn recruits several adaptor proteins, including the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K), growth factor receptor-bound protein 2 (GRB2), and GRB2-related adaptor protein 2 (GADS), to its YMNM motif, and these interactions activate mitogenactivated protein kinase (MAPK), nuclear factor of activated T cells (NFAT), nuclear factor-jB (NF-jB) and AKT, leading to T-cell activation, cytokine production and proliferation. Genetic alterations of the CD28 gene have been reported in haematologic malignancies including angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) or cutaneous T-cell lymphoma (CTCL). Using genome-wide sequencing, Kataoka et al. reported that the most common genetic alterations in adult T-cell leukaemia/lymphoma (ATL), which is a mature T-cell neoplasm associated with the human T-cell leukaemia virus type 1 (HTLV-1), involves the TCR–NF-jB signalling pathway. In RNA-seq analysis of 57 ATL samples, five CD28 fusions (CTLA4–CD28 and ICOS–CD28) were detected, where the 5’ part of the CTLA4 or ICOS genes was fused to the 30 part of the CD28 gene. These fusions arrange for the cytoplasmic portion of CD28 to be expressed under the control of the regulatory elements of CTLA4 or ICOS and may lead to constitutive CD28 signalling activation. Gain of function mutations (F51I/V and D124E/V) in the CD28 genes were also described in eight cases out of 370 cases (2%). The substitutions were located in the highly conserved B7 ligand-binding sites and the bases were replaced by amino acids specific to CTLA4 or ICOS. Furthermore, recurrent focal copy number gain was detected in the CD28 locus (75 of 426 cases, 18%). In their paper the authors investigated the association between CD28 gene alterations and clinical outcome in a cohort of ATL patients. As expected, they found gene fusions, activating mutations, and gene amplification in the CD28 genes. Among the 144 ATLL patients, gene fusions between ICOS exon 1 and CD28 exon 2 and between CTLA4 exon 3 and CD28 exon 4 were detected in 14 patients (10%) by multiplex reverse transcription polymerase chain reaction (RTPCR) analysis. Moreover, two types of CD28-activating mutations, F51I/V and D124E/V were detected in three patients (2%) by utilizing the SNaPshot method, and CD28 copy number gain or amplification was detected in 34 patients (24%) by fluorescence in situ hybridization (FISH) analysis. Notably, patients with CD28 gene alterations were revealed to be younger than those without (60 vs. 66 years). Allogeneic haematopoietic stem cell transplantation (HSCT) is the only Correspondence: Dr. Kazuhiro Morishita, Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. E-mail: [email protected] commentary