Down-regulation of CD5 expression on activated CD8+ T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled activation of T cells and macrophages with overproduction of cytokines. Familial HLH type2 (FHL2) is the most common form of primary HLH and is caused by mutations in PRF1. We have recently described a significant increase in the subpopulation of CD8 + T cells with clonal expansion and CD5 down-regulation in Epstein-Barr virus associated-HLH, which represented a valuable tool for its diagnosis. However, this unusual phenotype of CD8 + T cells has not been investigated fully in patients with FHL2. We performed immunophenotypic analysis of peripheral blood and measured serum proinflammatory cytokines in 5 patients with FHL2. All patients showed significantly increased subpopulations of activated CD8 + T cells with down-regulation of CD5, which were negligible among normal controls. Analysis of T-cell receptor Vβ repertoire suggested the reactive and oligoclonal expansion of these cells. The proportion of the subset declined after successful treatment concomitant with reduction in the serum levels of cytokines in all patients except one who continued to have a high proportion of the subset and died. These findings suggest that down-regulation of CD5 on activated CD8 +

Munc13‐4 deficiency with CD5 downregulation on activated CD8+ T cells

“…More importantly, a significant increase in the subpopulation of activated CD8 + T cells with downregulation of CD5 expression was demonstrated in the patient. These findings are similar to those of FHL2 . While the mechanism underlying downregulation of CD5 on activated CD8 + T cells remains to be elucidated, it is tempting to speculate that patients with any of the FHL subtypes other than FHL2 might also have downregulation of CD5 on activated CD8 + T cells during the acute phase.…”

“…It has recently been reported that CD5 is recruited and co‐localized with CD3 at the immunological synapse and inhibits T‐cell receptor (TCR) signaling in T cells without interfering with immunological synapse formation . In this report, we extended our previous observation and investigated a patient with FHL3 who had downregulation of CD5 on activated CD8 + T cells.…”

“…We have recently reported an increased subpopulation of activated CD8 + T cells with downregulation of CD5 expression in patients with FHL2 . This unique immunophenotypic feature may serve as a useful marker of dysregulated T‐cell activation and proliferation in FHL2 .…”

“…In contrast, a sizable proportion of CD5‐negative cells were detected among the activated CD8 + T cells. These findings prompted us to analyze perforin expression on flow cytometry in order to assess the possibility of FHL2 . NK cells from the patient, however, expressed perforin at a level similar to normal controls (data not shown).…”

Clinical analysis of 42 cases of EBV-positive mature T/NK-cell neoplasms

“…CD5 − status has been suggested to be an adverse prognostic factor (30), and the downregulation of CD5 expression in EBV-HLH has been reported to be associated with the serum levels of cytokines, and T cell activation and proliferation (31). In the present study, the IPI scores of CD5 − patients were clearly higher than those in CD5 + patients, and the mean survival time of CD5 − patients was shorter; moreover, an association between CD5 expression and OS was identified.…”