A Systemic Review of T Regulatory Cells and Their Role In Hodgkin and Non-Hodgkin Lymphoma
Abstract
Regulatory T cells (Tregs) know for monitoring and regulating the immune response in healthy individuals. In hematological malignancies, Tregs cells exert an immunosuppressive effect thus playing an important role in tumor progression and spread. It is a systemic review focusing on evolution and prognostic role of Tregs in hematological malignancies and the results are very conflicting. Different tissues (peripheral blood, Lymphnode tissue and bone marrow) were used for studies with applications of different methods like Flow cytometry on whole blood / isolated peripheral blood mononuclear cells with different gating techniques, Immunohistochemistry using different panel of monoclonal antibodies, which partially explained the confrontation of results. It is of particular importance to mention above finding to solidify the requirement of use of standardized approaches in study of Tregs in hematological malignancies and in cancer.References
Giovanni D’Arena et al. Regulatory T Cells and Their Prognostic Relevance inhematologic Malignancies. Hindawi Journal of Immunology ResearchVolume 2017, Article ID 1832968, 13 pages. https://doi.org/10.1155/2017/1832968
Lim HW, Hillsamer P, Banham AH, Kim CH. Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J Immunol. 2005;175:4180-4183.
Curiel TJ, Coukos G, Zou LH et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10:942–9.
Bates GJ, Fox SB, Han C et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 2006; 24:5373–80.
Petersen RP, Carnpa MJ, Sperlazza J et al. Tumor infiltrating FOXP3(+) regulatory T-cells are associated with recurrence in pathologic stage INSCLC patients. Cancer 2006; 107:2866–72.
Gao Q, Qiu SJ, Fan J et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007; 25:2586–93
Griffiths RW, Elkord E, Gilham DE et al. Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival. Cancer Immunol Immunother 2007; 56:1743–53.
Jensen HK, Donskov F, Nordsmark M, Marcussen N, von der Maase H. Increased Intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renalcell carcinoma. Clin Cancer Res 2009; 15:1052–8.
Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3(+) regulatory T cells increases during the progression of pancreatic ductal adenocarcinorna and its premalignant lesions.Clin Cancer Res 2006; 12:5423–34.
Jordanova ES, Gorter A, Ayachi O et al. Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8(+)/regulatory T-cell ratio: which variable determinessurvival of cervical cancer patients? Clin Cancer Res 2008;14:2028–35.
Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 2011; 60:909 18.
Salama P, Phillips M, Grieu F et al. Tumor-infiltrating FOXP3(+) T regulatory cells show strong prognostic significance in colorectalcancer. J Clin Oncol 2009; 27:186–92.
Nosho K, Baba Y, Tanaka N et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis:cohort study and literature review. J Pathol 2010; 222:350–66.
Tzankov A, Meier C, Hirschmann P, Went P, Pileri SA, Dirnhofer S. Correlation of high numbers of intratumoral FOXP3(+) regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma. Haematologica 2008; 93:193–200
Chang et al. Regulatory T Cells in Large B-Cell Lymphoma Am J Clin Pathol December 2015;144:935-944
Wei Wu et al. Functional role of regulatory T cells in B cell lymphoma and related mechanisms. Int J Clin Exp Pathol 2015;8(8):9133-9139
S. Schreck, D. Friebel, M. Buettner et al., “Prognostic impact of tumour-infiltrating Th2 and regulatory T cells in classical Hodgkin lymphoma,” Hematological Oncology, vol. 27, no. 1,pp. 31–39, 2009.
T. Alvaro, M. Lejeune, M. T. Salvado et al., “Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells,” Clinical Cancer Research, vol. 11, no. 4, pp. 1467–1473, 2005.
M. Garcia, B. Bellosillo, B. Sánchez-González et al., “Study of regulatory T-cells in patients with gastric Malt lymphoma: influence on treatment response and outcome,” PLoS One,vol. 7, no. 12, article e51681, 2012
R. K. Gershon and k. Kondo. “Cell Interactions in the Induction of Tolerance:The Role of Thymic Lymphocytes”, Immunology, 1970, 18, 723.
Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., and Toda, M. (1995). “Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains(CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases”. J. Immunol. 155, 1151–1164.
T Takahashi , Y Kuniyasu, M Toda, N Sakaguchi, M Itoh, M Iwata, J Shimizu, S Sakaguchi. (1998) “Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state ” International Immunology, 10(12), 1969–1980
Angela M. Thornton and Ethan M. Shevach, “CD41CD251 Immunoregulatory T Cells Suppress Polyclonal T Cell Activation In Vitro by Inhibiting Interleukin 2 Production. ” The Journal of Experimental Medicine • Volume 188, Number 2, July 20, 1998 287–296
Mary E. Brunkow, Eric W. Jeffery et al “ Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse”, February 2001,Nature Genetics 27(1):68-73,DOI:10.1038/83784
Khattri, R., Cox, T., Yasayko, S.-A., & Ramsdell, F. (2003). “ An essential role for Scurfin in CD4+ CD25+ T regulatory cells. Nature Immunology”, 4(4), 337–342. doi:10.1038/ni909
Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y. (2003). Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunology, 4(4), 330–336. doi:10.1038/ni904
Hori, S. (2003). Control of Regulatory T Cell Development by the Transcription Factor Foxp3. Science, 299(5609), 1057–1061. doi:10.1126/science.1079490
Deaglio S, Dwyer KM, Gao W et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007; 204:1257–65
Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 50-adenosine monophosphate to adenosine. J Immunol 2006;177:6780–6.
Bopp T, Becker C, Klein M et al. Cyclic adenosine monophosphate is a key componentof regulatory T cell-mediated suppression. J Exp Med 2007; 204:1303–10.
Novak TJ, Rothenberg EV. cAMP inhibits induction of interleukin 2 but not of interleukin4 in T cells. Proc Natl Acad Sci USA 1990; 87:9353–7.
Mahic M, Yaqub S, Johansson CC, Tasken K, Aandahl EM. FOXP3+ CD4+ CD25+adaptive regulatory T cells express cyclooxygenase-2 and suppress effector T cells by aprostaglandin E2-dependent mechanism. J Immunol 2006; 177:246–54.
Goto T, Herberman RB, Maluish A, Strong DM. Cyclic AMP as a mediator of prostaglandinE-induced suppression of human natural killer cell activity. J Immunol 1983;130:1350–5.
Lindqvist CA, Christiansson LH, Simonsson B, Enblad G, Olsson-Stromberg U, LoskogAS. T regulatory cells control T-cell proliferation partly by the release of soluble CD25in patients with B-cell malignancies. Immunology 2010; 131:371–6.
Shalev I, Schmelzle M, Robson SC, Levy G. Making sense of regulatory T cell suppressive function. Semin Immunol 2011; 23:282–92.
K. Oleinika, R. J. Nibbs, G. J. Graham and A. R. Fraser,Suppression, subversion and escape: the role of regulatory T cells in cancer progression. 2012 British Society for Immunology, Clinical and Experimental Immunology, 171: 36–45
Menetrier-Caux C, Curiel T, Faget J, Manuel M, Caux C, Zou W. Targeting regulatory T cells. Target Oncol 2012; 7:15–28.
Nizar S, Copier J, Meyer B et al. T-regulatory cell modulation: the future of cancer immunotherapy? Br J Cancer 2009; 100:1697–703.
Sutmuller RPM, van Duivenvoorde LM, van Elsas A et al. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001;194:823–32.
Quezada SA, Peggs KS, Simpson TR, Allison JP. Shifting the equilibrium in cancer immunoediting: from tumor tolerance toeradication. Immunol Rev 2011; 241:104–18.
Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S. Heterogeneity of natural Foxp3(+) T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA 2009;106:1903–8.
Hou XY, Bailey-Bucktrout SL, Jeker LT et al. Instability of thetranscription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 2009; 10:1000–U104
Linterman MA, Pierson W, Lee SK et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 2011; 17:975–82.
Chung Y, Tanaka S, Chu F et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med 2011; 17:983–8.
Xu L, Kitani A, Fuss I, Strober W. Cutting edge: regulatory T cells induce CD4+ CD25) Foxp3) T cells of are self-induced to become Th17 cells in the absence of exogenous TGF-b. J Immunol 2007; 178:6725–9.
Zhou X, Bailey-Bucktrout SL, Jeker LT et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol2009; 10:1000–7.
Mays LE, Chen YH. Maintaining immunological tolerance with Foxp3. Cell Res 2007;17:904–18
Fransson M, Burman J, Lindqvist C, Atterby C, Fagius J, Loskog A. T regulatory cells lacking CD25 are increased in MS during relapse. Autoimmunity 2010; 43:590–7.
Stephens LA, Mason D. CD25 is a marker for CD4+ thymocytes that prevent autoimmune diabetes in rats, but peripheral T cells with this function are found in both CD25+ and CD25) subpopulations. J Immunol 2000; 165:3105–10.
Yagi H, Nomura T, Nakamura K et al. Crucial role of FOXP3 in the development and function of human CD25+ CD4+ regulatory T cells. Int Immunol 2004; 16:1643–56.
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299:1057–61.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol 2003; 4:330–6
Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY Genome-wideanalysis of Foxp3 target genes in developing and mature regulatory T cells. Nature2007; 445:936–40
Banham AH. Cell-surface IL-7 receptor expression facilitates the purification ofFOXP3+ regulatory T cells. Trends Immunol 2006; 27:541–4.
Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+ CD4+ regulatory cells that control intestinalinflammation. J Exp Med 2000; 192:295–302.
Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S. Immunologic self-tolerance maintained by CD25+ CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192:303–10.
McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M, Byrne MC. CD4+ CD25+ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002; 16:311–23.
D. Catovsky, E. Miliani, A. Okos, D.A. Galton, Clinical significance of T-cells in chronic lymphocytic leukaemia, Lancet 2 (1974) 751–752.
F. Herrmann, A. Lochner, H. Philippen, B. Jauer, H. Ruhl, Imbalance of T cell subpopulations in patients with chronic lymphocytic leukaemia of the B cell type, Clin. Exp. Immunol. 49 (1982) 157–162.
Dasgupta, M. Mahapatra, and R. Saxena, “A study for proposal of use of regulatory T cells as a prognostic marker and establishing an optimal threshold level for their expression in chronic lymphocytic leukemia,” Leukemia & Lymphoma, vol. 56, no. 6, pp. 1831–1838, 2015.
Goivani. D’Arena, L. Laurenti, M. M. Minervini et al., “Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease,” Leukemia Research, vol. 35, no. 3, pp. 363–368,2011
J. Carrer as, A. Lopez-Guillermo, B. C. Fox et al., “High numbers of tumor-infiltrating FOXP3-positive regulatory T-cells are associated with improved overall survival in follicular lymphoma,” Blood, vol. 108, no. 9, pp. 2957–2964, 2006.
C. Chang, S. Y. Wu, Y. W. Kang et al., “High levels of regulatory T cells in blood are a poor prognostic factor in patients with diffuse large B-cell lymphoma,” American Journal Clinical Pathology, vol. 144, pp. 935–944, 2015.
Neil A. Marshall, Linsey E. Christie, Laura R. Munro et al, “Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. ” Blood, 1 march 2004 volume 103, number 5.
S. Schreck, Daniela Friebel, Maike Buettneret al.“Prognostic impact of tumour-infiltrating Th2 andregulatory T cells in classical Hodgkin lymphoma.” Hematol Oncol 2009; 27: 31–39
E.Gunduz, Serap Sermet, and Ahmet Musmul et al. “Peripheral Blood Regulatory T Cell Levels AreCorrelated with Some Poor Prognostic Markersin Newly Diagnosed Lymphoma Patients” Cytometry Part B (Clinical Cytometry) 90B:449–454 (2016).
Vassiliki E. Mpakoua, Heleni-Dikaia, Ioannidou, “ Quantitative and qualitative analysis of regulatory T cells in B cell chronic lymphocytic leukemia” Leukemia Research 60 (2017) 74–81.
Serag El-Dien, MD, Asmaa Getal, “ Intratumoral FOXP3+ Regulatory T Cells in Diffuse Large B-Cell Lymphoma” Appl Immunohistochem Mol Morphol 2016;00:000–000.
Ahmad Baraka and Hatem M. Salem, “Clinical Significance of T-Regulatory Cells in B-Cell Non-Hodgkin's Lymphoma” The Egyptian Journal of Immunology ,Vol. 18 (2), 2011Page: 23-30.
Petros Christopoulos, Dietmar Pfeifer et al“ Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL”. January 26, 2011; DOI 10.1182/blood-2010-07-299321.
A.Biancotto, Pradeep K Dagur, John C Fuchs et al “ Phenotypic complexity of T regulatory subsets in patients with B-chronic lymphocytic leukemia” Modern Pathology (2012) 25, 246–259.
Anne Rissiek, Christian Schulze, Ulrike Bacher et al.“Multidimensional scaling analysis identifies pathological and prognostically relevant profiles of circulating T-cells in chronic lymphocytic leukemia”. Int. J. Cancer: 135, 2370–2379 (2014).
Sajjan Mittal, Neil A. Marshall, Linda Duncan. “ Local and systemic induction of CD4,CD25regulatory T-cell population by non-Hodgkin lymphoma”.Blood, 1 june 2008 volume 111, number 11.
A Koreishi, AJ Saenz, DO Persky et al. “ The Role of Cytotoxic and Regulatory T-Cells in Relapsed/Refractory Hodgkin Lymphoma. ”Appl Immunohistochem Mol Morphol. 2010 May ; 18(3): 206–211
Copyright (c) 2024 Nishant Taur, Rashmi Kushwah, Mili Jain, Akansha Singh, Rahul Mittal
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access at http://opcit.eprints.org/oacitation-biblio.html).
