title: Critical stoichiometric ratio of CD4(+)  CD25(+)  FoxP3(+) regulatory T cells and CD4(+)  CD25(-) responder T cells influence immunosuppression in patients with B-cell acute lymphoblastic leukaemia.
abstract: Regulatory T (Treg) cells act to suppress activation of the immune system and thereby maintain immunological homeostasis and tolerance to self-antigens. The frequency and suppressing activity of Treg cells in general are high in different malignancies. We wanted to identify the role and regulation of CD4(+)  CD25(+)  FoxP3(+) Treg cells in B-cell acute lymphoblastic leukaemia (B-ALL). We have included patients at diagnosis (n = 54), patients in clinical remission (n = 32) and normal healthy individuals (n = 35). These diagnosed patients demonstrated a lower number of CD4(+)  CD25(+) cells co-expressing a higher level of FoxP3, interleukin-10, transforming growth factor-β and CD152/CTLA-4 than the normal population. Treg cells from patients showed a higher suppressive capability on CD4(+)  CD25(-) responder T (Tresp) cells than normal. The frequency and immunosuppressive potential of CD4(+)  CD25(+)  FoxP3(+) Treg cells became high with the progression of malignancy in B-ALL. Relative distribution of Tresp and Treg cells was only ~5 : 1 in B-ALL but ~35 : 1 in normal healthy individuals, further confirming the elevated immunosuppression in patients. A co-culture study at these definite ex vivo ratios, indicated that Treg cells from B-ALL patients exhibited higher immunosuppression than Treg cells from normal healthy individuals. After chemotherapy using the MCP841 protocol, the frequency of CD4(+)  CD25(+) cells was gradually enhanced with the reduction of FoxP3, interleukin-10 positivity corresponded with disease presentation, indicating reduced immunosuppression. Taken together, our study indicated that the CD4(+)  CD25(+)  FoxP3(+) Treg cells played an important role in immunosuppression, resulting in a positive disease-correlation in these patients. To the best of our knowledge, this is the first detailed report on the frequency, regulation and functionality of Treg cells in B-ALL.
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research - Indian Institute of Chemical Biology, Jadavpur, Kolkata, India.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Bhattacharya
authors.forename: Sarmila
authors.initials: S
authors.lastname: Chandra
authors.forename: Chitra
authors.initials: C
authors.lastname: Mandal
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016022:Case-Control Studies; D002454:Cell Differentiation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007223:Infant; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008297:Male; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000276:immunology*; D012074:Remission Induction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit
keywords: B-cell acute lymphoblastic leukaemia; FoxP3; immunosuppression; regulatory T cells; responder T cells