Background/aim: T lymphocytes are important players of the immune response. B-CLL is characterized by several immune defects. Our study aims to characterize the distinct maturational and functional T/NK cell subsets within B-cell chronic lymphocytic leukemia disease Rai stages. Patients and methods: Peripheral blood mononuclear cells from 43 patients enrolled in the study (16 females and 27 males, aged 68±10, 8 Rai 0, 22 Rai 1/2 and 13 Rai 3/4) were analyzed by multiparameter flow cytometry. Distinct subsets within the CD4+ (naive, central memory, effector/peripheral memory, regulatory-Tregs, follicular-TFH, CXCR3+ and/or CCR4+), CD8+ (naive+memory, effector, senescent) and NK (CD57+ and/or CD94+) were identified and compared between disease Rai stages. Results: Total numbers of T lymphocytes increase with disease stage. Both CD4+ and CD8+ T cells are elevated in absolute counts. The majority of CD4+ T cells are antigen-experienced, with increased Tregs, TFH and CXCR3+ (Th1-associated profile) T cell counts. The CD8+ T cells expansion is due mostly to the senescent CD57+ subset. No significant difference within NK subsets was observed among different disease stages. Conclusions: B-CLL behaviour seems to be associated with increased numbers of TFH and Tregs. The therapeutic modulation of T cell response in B-CLL patients may play an important role in the disease behaviour and may be a key event compensating for the immunodeficiency occurring mostly in advanced stages of the disease.
1. Hamblin TJ, Oscier DG, Young BJ. Autoimmunity in chronic lymphocytic leukaemia. J Clin Pathol. 1986;39(7):713-6.
2. Johnston P, Kay N. Pathogenesis of Impaired Cellular Immune Function in CLL. In: Faguet G, editor. Chronic Lymphocytic Leukemia. Contemporary Hematology: Humana Press; 2004. p. 109-21.
3. Vuillier F, Tortevoye P, Binet JL, Dighiero G. CD4, CD8 and NK subsets in B-CLL. Nouv Rev Fr Hematol. 1988;30(5-6):331-4.
4. Christopoulos P, Pfeifer D, Bartholome K, Follo M, Timmer J, Fisch P, et al. Definition and characterization of the systemic T-cell dysregulation in untreated indolent Bcell lymphoma and very early CLL. Blood. 2011;117(14):3836-46.
5. Gonzalez-Rodriguez AP, Contesti J, Huergo-Zapico L, Lopez-Soto A, Fernandez-Guizan A, Acebes-Huerta A, et al. Prognostic significance of CD8 and CD4 T cells in chronic lymphocytic leukemia. Leuk Lymphoma. 2010;51(10):1829-36.
6. Catovsky D, Miliani E, Okos A, Galton DA. Clinical significance of T-cells in chronic lymphocytic leukaemia. Lancet. 1974;2(7883):751-2.
7. Herrmann F, Lochner A, Philippen H, Jauer B, Ruhl H. Imbalance of T cell subpopulations in patients with chronic lymphocytic leukaemia of the B cell type. Clin Exp Immunol. 1982;49(1):157-62.
8. te Raa GD, Tonino SH, Remmerswaal EB, van Houte AJ, Koene HR, van Oers MH, et al. Chronic lymphocytic leukemia specific T-cell subset alterations are clone-size dependent and not present in monoclonal B lymphocytosis. Leuk Lymphoma. 2012;53(11):2321-5.
9. Mackus WJ, Frakking FN, Grummels A, Gamadia LE, De Bree GJ, Hamann D, et al. Expansion of CMV-specific CD8+CD45RA+CD27- T cells in B-cell chronic lymphocytic leukemia. Blood. 2003;102(3):1057-63.
10. Nunes C, Wong R, Mason M, Fegan C, Man S, Pepper C. Expansion of a CD8(+)PD-1(+) replicative senescence phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and disease progression. Clin Cancer Res. 2012;18(3):678-87.
11. Giannopoulos K, M Schmitt PW, lstrok. The high frequency of T regulatory cells in patients with B-cell chronic lymphocytic leukemia is diminished through treatment with thalidomide. Leukemia. 2007;22(1):222-4.
12. D’Arena G, Laurenti L, Minervini MM, Deaglio S, Bonello L, De Martino L, et al. Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease. Leuk Res. 2011;35(3):363-8.
13. Kay NE, Han L, Bone N, Williams G. Interleukin 4 content in chronic lymphocytic leukaemia (CLL) B cells and blood CD8+ T cells from B-CLL patients: impact on clonal B-cell apoptosis. Br J Haematol. 2001;112(3):760-7.
14. Mu X, Kay NE, Gosland MP, Jennings CD. Analysis of blood T-cell cytokine expression in B-chronic lymphocytic leukaemia: evidence for increased levels of cytoplasmic IL-4 in resting and activated CD8 T cells. Br J Haematol. 1997;96(4):733-5.
15. Cyster JG. Chemokines and cell migration in secondary lymphoid organs. Science. 1999;286(5447):2098-102.
16. Sallusto F. The role of chemokine receptors in primary, effector and memory immune response. Exp Dermatol. 2002;11(5):476-8.
17. Kim CH, Rott L, Kunkel EJ, Genovese MC, Andrew DP, Wu L, et al. Rules of chemokine receptor association with T cell polarization in vivo. J Clin Invest. 2001;108(9):1331-9.
18. Fuss IJ, Kanof ME, Smith PD, Zola H. Isolation of whole mononuclear cells from peripheral blood and cord blood. Curr Protoc Immunol. 2009;Chapter 7:Unit7 1.
19. Ahearne MJ, Willimott S, Pinon L, Kennedy DB, Miall F, Dyer MJ, et al. Enhancement of CD154/IL4 proliferation by the T follicular helper (Tfh) cytokine, IL21 and increased numbers of circulating cells resembling Tfh cells in chronic lymphocytic leukaemia. Br J Haematol. 2013;162(3):360 70.
20. Morita R, Schmitt N, Bentebibel S-E, Ranganathan R, Bourdery L, Zurawski G, et al. Human Blood CXCR5(+) CD4(+) T Cells Are Counterparts of T Follicular Cells and Contain Specific Subsets that Differentially Support Antibody Secretion. Immunity. 2011;34(1):108-21.
21. Ma J, Zhu C, Ma B, Tian J, Baidoo SE, Mao C, et al. Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis. Clin Dev Immunol. 2012;2012:827480.
22. Lindwall E, Gauthier C, Lyman J, Alarakhia A, Zakem J, Davis W, et al. Circulating T Helper Cells in Patients with Systemic Lupus Erythematosus Share the Phenotypic Property with Lymphoid T Follicular Helper Cells. Nat Immunol. 2010;11(6):464-6.
23. Li X-y, Wu Z-b, Ding J, Zheng Z-h, Li X-y, Chen Ln, et al. Role of the frequency of blood CD4(+) CXCR5(+) CCR6(+) T cells in autoimmunity in patients with Sjögren’s syndrome. Biochem Biophys Res Commun. 2012;422(2):238-44.
24. Piper KP, Karanth M, McLarnon A, Kalk E, Khan N, Murray J, et al. 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. Clin Exp Immunol. 2011;166(2):154-63.
25. Junevik K, Werlenius O, Hasselblom S, Jacobsson S, Nilsson-Ehle H, Andersson PO. The expression of NK cell inhibitory receptors on cytotoxic T cells in B-cell chronic lymphocytic leukaemia (B-CLL). Ann Hematol. 2007;86(2):89-94.
26. Rivino L, Messi M, Jarrossay D, Lanzavecchia A, Sallusto F, Geginat J. Chemokine receptor expression identifies pre-T helper (Th) 1, pre-Th2, and nonpolarized cells among human CD4+ central memory T cells. J Exp Med. 2004;200(6):725-35.
27. Podhorecka M, Dmoszynska A, Rolinski J, Wasik E. T type 1/type 2 subsets balance in B-cell chronic lymphocytic leukemia--the three-color flow cytometry analysis. Leuk Res. 2002;26(7):657-60.
28. Rossmann ED, Lewin N, Jeddi-Tehrani M, Osterborg A, Mellstedt H. Intracellular T cell cytokines in patients with B cell chronic lymphocytic leukaemia (B-CLL). Eur J Haematol. 2002;68(5):299-306.