Both CD4⁺ FoxP3⁺ and CD4⁺ FoxP3⁻ T cells from patients with B‐cell malignancy express cytolytic markers and kill autologous leukaemic B cells in vitro

Abstract

Summary Cytotoxic CD4+ T cells have been found in patients with chronic lymphocytic leukaemia (CLL) and seem to be involved in the regulation of malignant B cells. The CD4+ T regulatory cells (Tregs) can regulate various immune cells, including B cells, by inducing their apoptosis. Hence, different subgroups of CD4+ T cells may be involved in the regulation of malignant B cells. In this study, the cytotoxic phenotype and function of various CD4+ T‐cell subgroups were investigated in patients with B‐cell malignancies. Peripheral blood was collected from patients with CLL, various B‐cell lymphomas, healthy adult donors, children with precursor B‐cell acute lymphoblastic leukaemia (pre‐B ALL) and from healthy children. CD4+ T cells (CD3+ CD4+ FoxP3−), Tregs (CD3+ CD4+ CD127low FoxP3+) and CD127high FoxP3+ T cells (CD3+ CD4+ CD127high FoxP3+) were analysed for their expression of the cytolytic markers CD107a and Fas ligand. Patients with CLL had increased CD107a expression on all tested T‐cell subgroups compared with healthy donors. Similar results were found in patients with B‐cell lymphomas whereas the CD107a expression in children with pre‐B ALL was no different from that in healthy controls. Fas ligand expression was similar between patient cells and cells of healthy donors. CD4+ T cells and Tregs from patients with CLL and healthy donors were subsequently purified and cultured in vitro with autologous B cells. Both subgroups lysed B cells and killing was confirmed by granzyme ELISAs. In conclusion, cytotoxic populations of CD4+ T cells, including Tregs, are present in patients with B‐cell malignancy and may be an important factor in immune‐related disease control.

Follicular B Lymphomas Generate Regulatory T Cells via the ICOS/ICOSL Pathway and Are Susceptible to Treatment by Anti-ICOS/ICOSL Therapy

“…Additionally, Tregs are known to kill B cells through Fas-FasL interaction or through the release of cytolytic molecules (46,47). So, further study is needed to identify mechanisms involved in direct FL B cell inhibition.…”

Chronic lymphocytic leukaemia cells drive the global CD4+ T cell repertoire towards a regulatory phenotype and leads to the accumulation of CD4+ forkhead box P3+ T cells

“…8). Linqvist et al [46] looked at expression of cytolytic markers and tumour cell killing by CD4 + T cells in CLL patients and demonstrated that CD4 + T cells were capable of cell killing and increased expression of the cytolytic marker CD107a globally on all CD4…”

Aberrant expression of Treg-associated cytokine IL-35 along with IL-10 and TGF-β in acute myeloid leukemia

“…In previous studies, elevated percentages or levels of Treg cells were reported in the total T-cell population isolated from tumor tissues or peripheral blood in a variety of hematological malignancies, including B-cell non-Hodgkin lymphoma (17), Hodgkin lymphoma (18), chronic lymphocytic leukemia (19)(20)(21), multiple myeloma (22) and AML (5)(6)(7)(8). Treg cells accumulating in the peripheral circulation of AML patients mediate vigorous suppression via IL-10 and TGF-β as well as contact-dependent mechanisms (6).…”