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

Abstract

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


Introduction

Chronic lymphocytic leukemia (CLL) is the most common mature B-cell neoplasm in Western countries. It is characterized by the appearance of monoclonal CD5+CD19+ mature B-cells in the peripheral blood, lymphoid system, and bone marrow.11. Swerdlow SH, Jaffe ES, International Agency for Research on Cancer, World Health Organization. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008. The prevalence of the disease is higher in men compared to women and the estimated incidence is two to six cases per 100,000 people annually. At the time of diagnosis, approximately 31% of the patients are younger than 64 years and the average age is 72 years.11. Swerdlow SH, Jaffe ES, International Agency for Research on Cancer, World Health Organization. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008.,22. Seer Stat FactSheets: Chronic lymphocytic leukemia. National Cancer Institute 2009. Available from: http://seercancergov/statfacts/html/clylhtml
http://seercancergov/statfacts/html/clyl...

The clinical course of CLL is heterogeneous, and survival can vary from months to decades. Although most patients have an asymptomatic disease, there is a group of patients with aggressive CLL characterized by autoimmune hemolytic anemia, recurrent infections, immunodeficiency, and transformation to aggressive lymphoma, with an average life expectancy of less than three years.11. Swerdlow SH, Jaffe ES, International Agency for Research on Cancer, World Health Organization. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008.,33. Stilgenbauer S, Zenz T. Understanding and managing ultra high-risk chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2010;2010:481-8.

Several factors play an important role in the etiology of CLL, such as genetic predisposition related to the familiar history, environmental factors, and antigens/auto-antigens promoting division of precursor cells and clonal evolution.11. Swerdlow SH, Jaffe ES, International Agency for Research on Cancer, World Health Organization. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008.,44. Riches JC, Ramsay AG, Gribben JG. Chronic lymphocytic leukemia: an update on biology and treatment. Curr Oncol Rep. 2011;13(5):379-85. Moreover, the study of CLL genome by sequencing approaches revealed novel mutated genes, such as MYD88, NOTCH1, SF3B1, and XPO1, among others. Importantly, some of these genes may be considered as prognostic factors.55. Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011;208(7):1389-401.-66. Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475(7354):101-5. Comment in: Nat Rev Clin Oncol. 2011;8(8):447; Cancer Cell. 2011;20(1):5-7.

Another important aspect that modulates the outcome of the disease in CLL patients is the interaction between neoplastic B-cells with microenvironment substratum and T-cells. These interactions occur in organized structures termed pseudofollicular proliferative centers (PC), which are clusters of small lymphocytes dispersed in lymph nodes and bone marrow. Interestingly, PC are not visualized in any other B-cell neoplasm, and this structure is considered a hallmark of CLL.77. Caligaris-Cappio F, Ghia P. Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease?. J Clin Oncol. 2008;26(27):4497-503. Data in the literature suggest that the crosstalk between CLL B-cells, extracellular components of the microenvironment, and T-cells has an important impact on the physiopathology and evolution of the disease, mainly through regulation of CLL B-cell expansion, differentiation, and survival. Conversely, this crosstalk may also induce qualitative and quantitative changes in normal T-cells that could impact the fitness of the immune system of CLL patients.77. Caligaris-Cappio F, Ghia P. Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease?. J Clin Oncol. 2008;26(27):4497-503.

8. Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 7th ed. Philadelphia, Pa.: Elsevier Saunders; 2012.

9. 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.

Tables 1 and 2 summarize some characteristics of neoplastic B-cells and normal T-cells, respectively, that may impact in CLL physiopathology.

Table 1
Characteristics of CLL B-cells.
Table 2
Qualitative and quantitative changes in T-cells induced by CLL B-cells.

In addition to these changes in the T-cell compartment, recent data suggest an accumulation of memory T-cells in CLL patients that is associated with a more aggressive course of the disease.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.,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.,3030. Hofbauer JP, Heyder C, Denk U, Kocher T, Holler C, Trapin D, et al. Development of CLL in the TCL1 transgenic mouse model is associated with severe skewing of the T-cell compartment homologous to human CLL. Leukemia. 2011;25(9):1452-8.,3131. Walton JA, Lydyard PM, Nathwani A, Emery V, Akbar A, Glennie MJ, et al. Patients with B cell chronic lymphocytic leukaemia have an expanded population of CD4 perforin expressing T cells enriched for human cytomegalovirus specificity and an effector-memory phenotype. Br J Haematol. 2010;148(2):274-84. Therefore, this study aimed to discuss the possible involvement of memory T-cells in the physiopathology and clinical course of CLL.

Memory T-cells

T-cells play a crucial role in the immune system; they are critical for combating and controlling tumors and intracellular and extracellular pathogens, acting as cytotoxic cells (cytotoxic T-lymphocytes [CTL]) or assisting other immune cells (T-helper [Th] lymphocytes). Importantly, Th lymphocytes differentiate into subsets capable of producing different cytokine patterns and, therefore, exerting diverse helper functions.88. Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 7th ed. Philadelphia, Pa.: Elsevier Saunders; 2012.

The course of immune response can be briefly summarized by initial antigen-specific stimulation of naïve T-cells that results in activation, vigorous proliferation, and differentiation to specific effector T-cell subpopulations, which are capable of fighting pathogens and tumor cells.88. Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 7th ed. Philadelphia, Pa.: Elsevier Saunders; 2012.

After pathogen clearance, the majority of effector T-cells die due to lack of stimulation with participation of the proapoptotic protein B-cell lymphoma 2 interacting mediator of cell death (BIM).3232. Hildeman DA, Zhu Y, Mitchell TC, Bouillet P, Strasser A, Kappler J, et al. Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. Immunity. 2002;16(6):759-67. In the case of chronic activation of T-cells, these may undergo activation-induced cell death (AICD), a cell death regulatory mechanism mediated by the FAS/ FASL interaction.3333. Green DR. Fas Bim boom! Immunity. 2008;28(2):141-3. Comment in: Immunity. 2008; 28(2):197-205; Immunity. 2008;28(2):218-30; Immunity. 2008;28(2):206-17.-3434. Jameson SC, Masopust D. Diversity in T cell memory: an embarrassment of riches. Immunity. 2009;31(6):859-71. Together, this homeostatic mechanism attempts to restore the initial 'baseline' immune system and is defined as the contraction phase of immune response.

However, a small fraction of antigen-specific T-cells are resistant to cell death and become long-lived memory T-cells. These cells comprise a heterogeneous group that are more sensitive to low antigen concentrations and that survive in the body to give faster and more effective antigen-specific responses, providing immediate protection in peripheral tissues and the ability to confer secondary responses in lymph nodes.3434. Jameson SC, Masopust D. Diversity in T cell memory: an embarrassment of riches. Immunity. 2009;31(6):859-71.

Criteria such as immediate effector function, phenotypic diversity, proliferative index, migratory capability, and anatomical location are used to define memory T-cells in human models and characterize them in central memory (TCM) and effector memory (TEM) profiles (Table 3). This classification was proposed in 1999 by Sallusto et al. and is now widely accepted in the international scientific literature.3535. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401(6754):708-12. Comment in: Nature. 1999;401(6754):659-60.,3636. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745-63.

Table 3
Central and effector memory T-cell characteristics.

CLL and memory T-cells

As previously mentioned, constant interaction with the microenvironment substratum and T-cells is essential for CLL B-cells in order to avoid apoptosis and acquire favorable growing conditions. As a result of this crosstalk, some changes in T-cells are well documented, but a recent observation that CLL is able to interfere in naïve and memory T-cell status deserves more discussion.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.,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.,3030. Hofbauer JP, Heyder C, Denk U, Kocher T, Holler C, Trapin D, et al. Development of CLL in the TCL1 transgenic mouse model is associated with severe skewing of the T-cell compartment homologous to human CLL. Leukemia. 2011;25(9):1452-8.,3131. Walton JA, Lydyard PM, Nathwani A, Emery V, Akbar A, Glennie MJ, et al. Patients with B cell chronic lymphocytic leukaemia have an expanded population of CD4 perforin expressing T cells enriched for human cytomegalovirus specificity and an effector-memory phenotype. Br J Haematol. 2010;148(2):274-84.

It has been demonstrated that CLL patients have a significant skewing only in the CD4 T-cell compartment towards TCM and TEM cells.3737. Pepper M, Jenkins MK. Origins of CD4(+) effector and central memory T cells. Nat Immunol. 2011;12(6):467-71. Interestingly, this altered T-cell profile was associated with a more aggressive course of the disease, as shown by the positive association with unmutated human immunoglobulin heavy chain variable genes (IgVH), advanced regent admission index clinical stage, and shorter treatment-free survival. Conversely, there was no correlation between the increase in CD4 memory T-cells and CD38 expression or genomic aberrations in CLL patients.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.

Another study demonstrated that a CLL mouse model had decreased naïve T-cells with concomitant increase in antigenexperienced memory T-cells, mainly the subtypes that have the ability to migrate to lymph nodes.3030. Hofbauer JP, Heyder C, Denk U, Kocher T, Holler C, Trapin D, et al. Development of CLL in the TCL1 transgenic mouse model is associated with severe skewing of the T-cell compartment homologous to human CLL. Leukemia. 2011;25(9):1452-8. As the background of the mouse model used was the TCL1, which represents an aggressive CLL, it is possible that the increased numbers of memory T-cells are related to the aggressiveness of CLL, both in humans and mice.

An interesting question is how the different types of memory T-cells could influence CLL physiopathology. It has been postulated that chronic antigenic stimulation through the B-cell receptor (BCR) is required for the neoplastic clone to survive and grow.3838. Stevenson FK, Caligaris-Cappio F. Chronic lymphocytic leukemia: revelations from the B-cell receptor. Blood. 2004;103(12):4389-95. In this context, CD4 TCM cells have the capability to migrate to the lymph nodes due to their expression of CXCR5 (a chemokine CXCL13-receptor produced by B-cells in lymph node follicles), and could interact with CLL B-cells, providing co-stimulatory signals, such as CD40L and cytokines.3636. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745-63. This crosstalk could contribute to a stronger BCR signaling, greater survival, expansion, and evolution of CLL.

In addition, according to the literature on memory T-cell generation, a low but sufficient activation of naïve T-cells is crucial to the differentiation of TCM cells.3939. Lanzavecchia A, Sallusto F. Understanding the generation and function of memory T cell subsets. Curr Opin Immunol. 2005;17(3):326-32. Associating this evidence with the fact that CLL B-cells are poor as antigen presenting cells,1111. 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. the interaction between CLL B-cells and naïve T-cells could result in a weak stimulation leading to the generation and/or accumulation of CD4 TCM cells.

Regarding TEM cells, cytokine production of interleukin-4 (IL-4) and interferon-gamma (IFN-γ) could also participate in CLL progression, mainly through the up-regulation of BCL-2 and protection of CLL cells from apoptosis.4040. Dancescu M, Rubio-Trujillo M, Biron G, Bron D, Delespesse G, Sarfati M. Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression. J Exp Med. 1992;176(5):1319-26.,4141. Buschle M, Campana D, Carding SR, Richard C, Hoffbrand AV, Brenner MK. Interferon gamma inhibits apoptotic cell death in B cell chronic lymphocytic leukemia. J Exp Med. 1993;177(1):213-8. It was demonstrated that, in in vitro co-culture assays, the apoptosis rate of CLL B-cells in the presence of CD4 TEM cells was lower than in other conditions, such as in the presence of either naïve CD4 T-cells or peripheral blood mononuclear cells. Moreover, the protection conferred by CD4 TEM cells seems to depend on IL-4.1919. 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.

Considered together, the existence of an intrinsic feedback mechanism involved in the physiopathology of the CLL is supported, in which CLL B-cells could induce the generation and/or accumulation of CD4 memory T-cells, which, in turn, would help them achieve better survival and expansion (Figure 1). Indeed, it was demonstrated that CD4 memory T-cell generation is impaired in mice that are deficient in B-cells.3737. Pepper M, Jenkins MK. Origins of CD4(+) effector and central memory T cells. Nat Immunol. 2011;12(6):467-71.,4242. Whitmire JK, Asano MS, Kaech SM, Sarkar S, Hannum LG, Shlomchik MJ, et al. Requirement of B cells for generating CD4+ T cell memory. J Immunol. 2009;182(4):1868-76.

Figure 1
Immunological crosstalk between chronic lymphocytic leukemia B-cells and CD4 T-cells.

At the lymph node site, neoplastic B-cells interact with naïve and activated CD4 T-cells, resulting in generation/ accumulation of CD4 memory T-cells in peripheral blood. Through the lymph node homing receptors, chemokine receptors and co-stimulatory CD4 central memory T-cells could offer survival signals to chronic lymphocytic leukemia B-cells at lymph node sites. In addition, cytokines produced by CD4 effector memory T-cells, such as interleukin-4 and interferongamma, could also participate in this survival process.

Unpublished data from our group supports the aforementioned information. Briefly, we analyzed the peripheral blood T-cells of 21 CLL patients, and evaluated whether the distribution of naïve and memory T-cells was related to the ZAP-70 expression, a well-established prognosis factor in CLL.4343. Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348(18):1764-75. Comment in: N Engl J Med. 2003;349(5):506-7; author reply 506-7; N Engl J Med. 2003;348(18):1797-9. Interestingly, this analysis demonstrated that ZAP-70 positive patients with neoplastic B-cells presented increased frequency and absolute numbers of CD4 TCM cells compared to the ZAP-70 negative patients and 17 age-matched healthy individuals (Correia RP, unpublished data). Although other clinical and laboratorial prognostic markers were not analyzed at this point, the results are in accordance with the literature that shows alterations in the memory CD4 T-cell subpopulations. Importantly, it is suggested that this alteration is restricted to the T-helper compartment, since no significant differences were observed among memory CD8 T-cells.

To the authors' knowledge, there is no study that evidences associations between genetic factors and T-cell skewing towards memory status. Because the authors believe that this information is critical for a better evaluation of the prognostic value of analyzing the memory T-cell compartment, as well as for the understanding of the involvement of CD4 memory T-cells in the pathophysiology of CLL, studies with this focus are underway in this laboratory.

Conclusions

Abnormalities in T-cell subsets may be associated with the progression of CLL. Particularly, the increased CD4 memory T-cells could help CLL B-cells to achieve better fitness, i.e., more survival and proliferation signals. Therefore, understanding and unraveling this mechanism could improve the prognostic information and therapeutic approaches in CLL.

REFERENCES

  • 1
    Swerdlow SH, Jaffe ES, International Agency for Research on Cancer, World Health Organization. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008.
  • 2
    Seer Stat FactSheets: Chronic lymphocytic leukemia. National Cancer Institute 2009. Available from: http://seercancergov/statfacts/html/clylhtml
    » http://seercancergov/statfacts/html/clylhtml
  • 3
    Stilgenbauer S, Zenz T. Understanding and managing ultra high-risk chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2010;2010:481-8.
  • 4
    Riches JC, Ramsay AG, Gribben JG. Chronic lymphocytic leukemia: an update on biology and treatment. Curr Oncol Rep. 2011;13(5):379-85.
  • 5
    Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011;208(7):1389-401.
  • 6
    Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475(7354):101-5. Comment in: Nat Rev Clin Oncol. 2011;8(8):447; Cancer Cell. 2011;20(1):5-7.
  • 7
    Caligaris-Cappio F, Ghia P. Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease?. J Clin Oncol. 2008;26(27):4497-503.
  • 8
    Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 7th ed. Philadelphia, Pa.: Elsevier Saunders; 2012.
  • 9
    Riches JC, Ramsay AG, Gribben JG. T-cell function in chronic lymphocytic leukaemia. Semin Cancer Biol. 2010;20(6):431-8.
  • 10
    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.
  • 11
    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.
  • 12
    Gorczynski RM, Lee L, Boudakov I. Augmented induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R. Transplantation. 2005;79(4):488-91.
  • 13
    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.
  • 14
    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.
  • 15
    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.
  • 16
    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.
  • 17
    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.
  • 18
    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.
  • 19
    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.
  • 20
    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.
  • 21
    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.
  • 22
    Cantwell M, Hua T, Pappas J, Kipps TJ. Acquired CD40-ligand deficiency in chronic lymphocytic leukemia. Nat Med. 1997;3(9):984-9.
  • 23
    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.
  • 24
    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.
  • 25
    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.
  • 26
    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.
  • 27
    Zenz T. Exhausting T cells in CLL. Blood. 2013;121(9):1485-6.
  • 28
    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.
  • 29
    Ysebaert L. T-cells in CLL: lost in migration. Blood. 2013;121(14):2580-2.
  • 30
    Hofbauer JP, Heyder C, Denk U, Kocher T, Holler C, Trapin D, et al. Development of CLL in the TCL1 transgenic mouse model is associated with severe skewing of the T-cell compartment homologous to human CLL. Leukemia. 2011;25(9):1452-8.
  • 31
    Walton JA, Lydyard PM, Nathwani A, Emery V, Akbar A, Glennie MJ, et al. Patients with B cell chronic lymphocytic leukaemia have an expanded population of CD4 perforin expressing T cells enriched for human cytomegalovirus specificity and an effector-memory phenotype. Br J Haematol. 2010;148(2):274-84.
  • 32
    Hildeman DA, Zhu Y, Mitchell TC, Bouillet P, Strasser A, Kappler J, et al. Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. Immunity. 2002;16(6):759-67.
  • 33
    Green DR. Fas Bim boom! Immunity. 2008;28(2):141-3. Comment in: Immunity. 2008; 28(2):197-205; Immunity. 2008;28(2):218-30; Immunity. 2008;28(2):206-17.
  • 34
    Jameson SC, Masopust D. Diversity in T cell memory: an embarrassment of riches. Immunity. 2009;31(6):859-71.
  • 35
    Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401(6754):708-12. Comment in: Nature. 1999;401(6754):659-60.
  • 36
    Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745-63.
  • 37
    Pepper M, Jenkins MK. Origins of CD4(+) effector and central memory T cells. Nat Immunol. 2011;12(6):467-71.
  • 38
    Stevenson FK, Caligaris-Cappio F. Chronic lymphocytic leukemia: revelations from the B-cell receptor. Blood. 2004;103(12):4389-95.
  • 39
    Lanzavecchia A, Sallusto F. Understanding the generation and function of memory T cell subsets. Curr Opin Immunol. 2005;17(3):326-32.
  • 40
    Dancescu M, Rubio-Trujillo M, Biron G, Bron D, Delespesse G, Sarfati M. Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression. J Exp Med. 1992;176(5):1319-26.
  • 41
    Buschle M, Campana D, Carding SR, Richard C, Hoffbrand AV, Brenner MK. Interferon gamma inhibits apoptotic cell death in B cell chronic lymphocytic leukemia. J Exp Med. 1993;177(1):213-8.
  • 42
    Whitmire JK, Asano MS, Kaech SM, Sarkar S, Hannum LG, Shlomchik MJ, et al. Requirement of B cells for generating CD4+ T cell memory. J Immunol. 2009;182(4):1868-76.
  • 43
    Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348(18):1764-75. Comment in: N Engl J Med. 2003;349(5):506-7; author reply 506-7; N Engl J Med. 2003;348(18):1797-9.

Publication Dates

  • Publication in this collection
    Jan-Feb 2014

History

  • Received
    12 Aug 2013
  • Accepted
    16 Oct 2013
Associação Brasileira de Hematologia e Hemoterapia e Terapia Celular R. Dr. Diogo de Faria, 775 cj 114, 04037-002 São Paulo/SP/Brasil, Tel. (55 11) 2369-7767/2338-6764 - São Paulo - SP - Brazil
E-mail: secretaria@rbhh.org