Involvement of memory T-cells in the pathophysiology of
               chronic lymphocytic leukemia

Correia, Rodolfo Patussi; Silva, Flávia Amoroso Matos e; Bacal, Nydia Strachman; Campregher, Paulo Vidal; Hamerschlak, Nelson; Amarante-Mendes, Gustavo P.

doi:10.5581/1516-8484.20140015

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Review articles • Rev Bras Hematol Hemoter 36 (1) • Jan-Feb 2014 • https://doi.org/10.5581/1516-8484.20140015 copy

Involvement of memory T-cells in the pathophysiology of chronic lymphocytic leukemia

Authorship SCIMAGO INSTITUTIONS RANKINGS

The role of T-cells in the pathogenesis of chronic lymphocytic leukemia has recently gained much attention due to the importance of the constant interaction between neoplastic B-cells with microenvironment substratum and T-cells. It is believed that these interactions modulate the clinical course of the disease, mainly through the regulation of the expansion, differentiation, and survival of chronic lymphocytic leukemia B-cells. Importantly, this crosstalk may also change the number, function, and memory phenotype of normal T-cells, thereby altering the amplitude and/or efficiency of adaptive immunity in chronic lymphocytic leukemia patients. The present study presents an overview on important aspects of this immunological crosstalk, particularly on the abnormalities of chronic lymphocytic leukemia B-cells and the alterations in normal T-cells, with focus on the CD4 memory T-cell compartment that could offer survival signals to chronic lymphocytic leukemia B-cell clone(s) and contribute to the establishment and progression of the disease. The authors believe that understanding the biological consequences of the interaction between normal T- and neoplastic B-cells in chronic lymphocytic leukemia may allow for improvements in the prognostic information and therapeutic approaches for this disease.

Leukemia lymphocytic chronic; B-cell; T-lymphocytes; Immunologic memory

Characteristics	Implications
Reduction in CD80/CD86 expression	CLL B-cells are poor antigen presenting cells¹¹11. Dazzi F, D'Andrea E, Biasi G, De Silvestro G, Gaidano G, Schena M, et al. Failure of B-cells of chronic lymphocytic leukemia in presenting soluble and alloantigens. Clin Immunol Immunopathol. 1995;75(1):26-32.
CD200 expression	Inhibition of T-helper-1 and induction of regulatory T-cells (Tregs)¹²12. Gorczynski RM, Lee L, Boudakov I. Augmented induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R. Transplantation. 2005;79(4):488-91.^,¹³13. Wong KK, Khatri I, Shaha S, Spaner DE, Gorczynski RM. The role of CD200 in immunity to B cell lymphoma. J Leukoc Biol. 2010;88(2):361-72.
Expression of FASL with downregulation of FAS	Protection of CLL B-cells from FAS-mediated cell death; promotion of T-cell apoptosis⁹9. Riches JC, Ramsay AG, Gribben JG. T-cell function in chronic lymphocytic leukaemia. Semin Cancer Biol. 2010;20(6):431-8.
Increase of soluble FAS	Related to the progressive CLL¹⁴14. Osorio LM, Aguilar-Santelises M, De Santiago A, Hachiya T, Mellstedt H, Jondal M. Increased serum levels of soluble Fas in progressive B-CLL. Eur J Haematol. 2001;66(5):342-6.
Secretion of soluble interleukin-2 receptor and interleukin-10	Inhibition of T-helper-1 differentiation¹⁵15. de Waal Malefyt R, Haanen J, Spits H, Roncarolo MG, te Velde A, Figdor C, et al. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991;174(4):915-24.^,¹⁶16. Lindqvist CA, Christiansson LH, Simonsson B, Enblad G, Olsson-Stromberg U, Loskog AS. T regulatory cells control T-cell proliferation partly by the release of soluble CD25 in patients with B-cell malignancies. Immunology. 2010;131(3):371-6.
Interleukin-6 secretion	Protection of CLL B-cells from spontaneous apoptosis; secretion of interleukin-4 by T-cells and consequent positive impact on CLL B-cell survival¹⁷17. Reittie JE, Yong KL, Panayiotidis P, Hoffbrand AV. Interleukin-6 inhibits apoptosis and tumour necrosis factor induced proliferation of B-chronic lymphocytic leukaemia. Leuk Lymphoma. 1996;22(1-2):83-90, follow. 186, color plate VI.^,¹⁸18. Buggins AG, Patten PE, Richards J, Thomas NS, Mufti GJ, Devereux S. Tumor-derived IL-6 may contribute to the immunological defect in CLL. Leukemia. 2008;22(5):1084-7.

Changes in T-cell	Comments
Increase in CD4 and CD8 T-cell absolute number	Due to leukocytosis⁹9. Riches JC, Ramsay AG, Gribben JG. T-cell function in chronic lymphocytic leukaemia. Semin Cancer Biol. 2010;20(6):431-8.^,¹⁰10. Scrivener S, Goddard RV, Kaminski ER, Prentice AG. Abnormal T-cell function in B-cell chronic lymphocytic leukaemia. Leuk Lymphoma. 2003;44(3):383-9.^,¹⁹19. Tinhofer I, Weiss L, Gassner F, Rubenzer G, Holler C, Greil R. Difference in the relative distribution of CD4+ T-cell subsets in B-CLL with mutated and unmutated immunoglobulin (Ig) VH genes: implication for the course of disease. J Immunother. 2009;32(3):302-9.
Inversion of the CD4/CD8 ratio in peripheral blood	CD4 T-cells are more sensitive to FAS mediated cell death²⁰20. Tinhofer I, Marschitz I, Kos M, Henn T, Egle A, Villunger A, et al. Differential sensitivity of CD4+ and CD8+ T lymphocytes to the killing efficacy of Fas (Apo-1/CD95) ligand+ tumor cells in B chronic lymphocytic leukemia. Blood. 1998;91(11):4273-81.^,²¹21. Pourgheysari B, Bruton R, Parry H, Billingham L, Fegan C, Murray J, et al. The number of cytomegalovirus-specific CD4+ T cells is markedly expanded in patients with B-cell chronic lymphocytic leukemia and determines the total CD4+ T-cell repertoire. Blood. 2010;116(16):2968-74. Comment in: Blood. 2010;116(16):2869-70.
Elevated expression of FAS	Increased rates of T-cell apoptosis induced by FASL on CLL B-cells²⁰20. Tinhofer I, Marschitz I, Kos M, Henn T, Egle A, Villunger A, et al. Differential sensitivity of CD4+ and CD8+ T lymphocytes to the killing efficacy of Fas (Apo-1/CD95) ligand+ tumor cells in B chronic lymphocytic leukemia. Blood. 1998;91(11):4273-81.
Deficiency acquired in CD40L expression	CLL cells induce downregulation of CD40L on the T-cell surface²²22. Cantwell M, Hua T, Pappas J, Kipps TJ. Acquired CD40-ligand deficiency in chronic lymphocytic leukemia. Nat Med. 1997;3(9):984-9.
Abnormal profile of cytokine and/or cytokine receptor expression¹⁰10. Scrivener S, Goddard RV, Kaminski ER, Prentice AG. Abnormal T-cell function in B-cell chronic lymphocytic leukaemia. Leuk Lymphoma. 2003;44(3):383-9.	-
Expansion of regulatory T-cells (Tregs)	Induced by CD200 expression in CLL B-cells¹²12. Gorczynski RM, Lee L, Boudakov I. Augmented induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R. Transplantation. 2005;79(4):488-91.^,¹³13. Wong KK, Khatri I, Shaha S, Spaner DE, Gorczynski RM. The role of CD200 in immunity to B cell lymphoma. J Leukoc Biol. 2010;88(2):361-72.
Reduction in T-cell receptor repertoire	T-cell oligloclonal expansion²³23. Rezvany MR, Jeddi-Tehrani M, Osterborg A, Kimby E, Wigzell H, Mellstedt H. Oligoclonal TCRBV gene usage in B-cell chronic lymphocytic leukemia: major perturbations are preferentially seen within the CD4 T-cell subset. Blood. 1999;94(3):1063-9.
Interleukin-4 secretion	Induced by interleukin-6secretion of CLL B-cells¹⁷17. Reittie JE, Yong KL, Panayiotidis P, Hoffbrand AV. Interleukin-6 inhibits apoptosis and tumour necrosis factor induced proliferation of B-chronic lymphocytic leukaemia. Leuk Lymphoma. 1996;22(1-2):83-90, follow. 186, color plate VI.^,¹⁸18. Buggins AG, Patten PE, Richards J, Thomas NS, Mufti GJ, Devereux S. Tumor-derived IL-6 may contribute to the immunological defect in CLL. Leukemia. 2008;22(5):1084-7.^,²⁴24. 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.
Cytoskeleton changes	Defective immune synapse²⁵25. Ramsay AG, Johnson AJ, Lee AM, Gorgun G, Le Dieu R, Blum W, et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Invest. 2008;118(7):2427-37.
Alterations in genes involved in CD8 T-cell cytotoxicity	Inefficient CD8 T-cellcytotoxicity²⁶26. Gorgun G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest. 2005;115(7):1797-805.^,²⁷27. Zenz T. Exhausting T cells in CLL. Blood. 2013;121(9):1485-6.
Defective lymphocyte function-associated antigen 1-directed T-cell motility	CLL B-cells alter the Rho GTPase signaling²⁸28. Ramsay AG, Evans R, Kiaii S, Svensson L, Hogg N, Gribben JG. Chronic lymphocytic leukemia cells induce defective LFA-1directed T-cell motility by altering Rho GTPase signaling that is reversible with lenalidomide. Blood. 2013;121(14):2704-14.^,²⁹29. Ysebaert L. T-cells in CLL: lost in migration. Blood. 2013;121(14):2580-2.

	Central memory T-cells	Effector memory T-cells
Anatomical location	Lymph nodes	Liver, lung, and gut
Effector function	Low	High/immediate
Proliferative index	High	Low
Migratory capability	Secondary lymphoid organs (CD62L^highCCR7^high)	Non-lymphoid tissues (CD62L^lowCCR7^low)
Cytokine pattern	IL-2	CD4: IFN-y, IL-4, andIL-17 CD8: perforin and granzyme
Co-stimulatory molecule	High expression of CD40L	-

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[1] Corresponding author at: UHospital Israelita Albert Einstein, Laboratório de Patologia Clínica. Avenida Albert Einstein, 627, Morumbi, 05652900, São Paulo, SP, Brazil. E-mail address: rodolfoptc@gmail.com (R.P. Correia).