Oligoclonal expansion of TCR Vδ T cells may be a potential immune biomarker for clinical outcome of acute myeloid leukemia

Abstract

BackgroundRecent data have shown that γδ T cells can act as mediators for immune defense against tumors. Our previous study has demonstrated that persisting clonally expanded TRDV4 T cells might be relatively beneficial for the outcome of patients with T cell acute lymphoblastic leukemia after hematopoietic stem cell transplantation (HSCT). However, little is known about the distribution and clonality of the TRDV repertoire in T cell receptor (TCR) of γδ T cells and their effects on the clinical outcome of patients with acute myeloid leukemia (AML). The aim of this study was to assess whether the oligoclonal expansion of TCR Vδ T cells could be used as an immune biomarker for AML outcome.Findingsγδ T cells were sorted from the peripheral blood of 30 patients with untreated AML and 12 healthy donors. The complementarity-determining region 3 (CDR3) sizes of eight TCR Vδ subfamily genes (TRDV1 to TRDV8) were analyzed in sorted γδ T cells using RT-PCR and GeneScan. The most frequently expressed TRDV subfamilies in the AML patients were TRDV8 (86.67 %) and TRDV2 (83.33 %), and the frequencies for TRDV1, TRDV3, TRDV4, and TRDV6 were significantly lower than those in healthy individuals. The most frequent clonally expanded TRDV subfamilies in the AML patients included TRDV8 (56.67 %) and TRDV4 (40 %). The clonal expansion frequencies of the TRDV2 and TRDV4 T cells were significantly higher than those in healthy individuals, whereas a significantly lower TRDV1 clonal expansion frequency was observed in those with AML. Moreover, the oligoclones of TRDV4 and TRDV8 were independent protective factors for complete remission. Furthermore, the oligoclonal expansion frequencies of TRDV5 and TRDV6 in patients with relapse were significantly higher than those in non-recurrent cases.ConclusionsTo the best of our knowledge, we characterized for the first time a significant alteration in the distribution and clonality of the TRDV subfamily members in γδ T cells sorted from AML patients. Clonally expanded TRDV4 and TRDV8 T cells might contribute to the immune response directed against AML, while oligoclonal TRDV5 and TRDV6 might occur in patients who undergo relapse. While the function of such γδ T cell clones requires further investigation, TRDV γδ T cell clones might be potential immune biomarkers for AML outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0353-3) contains supplementary material, which is available to authorized users.

A skewed distribution and increased PD-1+Vβ+CD4+/CD8+ T cells in patients with acute myeloid leukemia

“…Previous studies have shown different proliferation patterns of TCR subfamily T cells between different subtypes and different disease statuses in leukemia at the molecular level . In this study, we also found a different distribution pattern of TCR Vβ subfamily T cells, particularly PD‐1+ Vβ subfamily T cells, between M5 and the favorable prognosis subtype M3.…”

“…Previous studies have shown different proliferation patterns of TCR subfamily T cells between different subtypes and different disease statuses in leukemia at the molecular level. 40,41 In this study, we also found a different distribution pattern of TCR V subfamily T cells, particularly PD-1+ V subfamily T cells, between M5 and the favorable prognosis subtype M3. However, there are only 3 cases with M5, so it is hard to perform the statistical analysis; we only observed the trends of alteration of PD-1+ V +T cells in both group, providing preliminary data regarding the association of PD-1+V + CD8+ T cells and the prognosis of AML.…”

Higher PD-1 expression concurrent with exhausted CD8+ T cells in patients with de novo acute myeloid leukemia

“…Previous studies have shown that such T cell immunodeficiencies are characterized by peripheral T cells that are incapable of interacting with blasts, reduced thymic output function, and oligoclonally restricted T cell repertoires, and led to low activation and low antigen responses. Moreover, the immunosuppressive microenvironment, including dysregulation of Th subset cytokines in the bone marrow, where both the innate and adaptive immune responses are profoundly deregulated, sustains and modulates the proliferation, survival, and drug resistance of AML (4)(5)(6)(7)(8)(9)(10).…”

Aplastic anemia is related to alterations in T cell receptor signaling

“…The coinhibitory cytotoxic T-lymphocyte associated protein 4 (CTLA-4), which is expressed on activated T cells also binds to CD80 or CD86 and interrupts T cell activation (15,16). After TCR ligation by specific antigens, T cells are stimulated to proliferate and differentiate into the cytotoxic effectors Th1 and Th2 helper cells, regulatory T cells, Th17 cells, or follicular helper T cells, which are influenced by the cytokine milieu and strength and duration of the TCR signal (17,18).…”