Diversity of regulatory T cells in various immuno-physiological conditions

Ganapathi Bhat M., Pooja Shahapurkar, R. D. Lele, Harish Ahuja


Background: Regulatory T cells (Tregs) play an active role in abrogating immune responses during microbial infections and are thus essential to maintain immune homeostasis and self-tolerance. Aberrant expression of Tregs can lead to spectrum of manifestations from allergy, chronic infections to immunopathological conditions such as autoimmunity and cancer. It is critical to have a clear understanding about the Tregs biology before attempting any possible interventions in humans. This study was undertaken to analyze the differential expression of Tregs in various physiological conditions.

Methods: Peripheral blood mononuclear cells (PBMCs) were extracted from normal human subjects (n=30), pregnant females (n=10), cord blood (n=10) and patients with various immunopathological conditions such as cancer (newly diagnosed non-Hodgkin’s lymphoma, n=10), autoimmune conditions such as (type 1 diabetes mellitus-T1DM, Hashimoto’s disorder, and other autoimmune disorders, n=10 each) and in donor grafts (n=10) following allogeneic hematopoietic stem cell transplant. Flow cytometry was performed to detect CD4+CD25+FOXP3+Tregs and CD4+CD25+CD127dim/-Tregs.

Results: The levels of Tregs was found to be were significantly higher in cord blood from newborn infants, patients with T1DM and Hashimoto’s disorder. In addition, the difference in Tregs level in pregnant females, patients with stem cell transplants, non-Hodgkin’s lymphoma and other autoimmune disorders were not significant.

Conclusions: Till date, no comparative study was available about the status of Tregs population in normal and different physiological conditions from India. This is the first preliminary quantitative analysis of association of Tregs with different disorders. A clear cognizance of Tregs biology among various physiological conditions will be vital for targeting of these cells for any possible therapeutic modalities.


Immuno-physiological, Cord blood, Autoimmunity, Cancer, T1DM, Pregnancy

Full Text:



Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531-62.

Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM. CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25− T cells. Blood. 2007;110:2537-44.

Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, et al. Regulatory T cells: recommendations to simplify the nomenclature. Nature immunology. Nature Publishing Group. 2013;14:307-8.

Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057-61.

Taams LS, van Amelsfort JMR, Tiemessen MM, Jacobs KMG, de Jong EC, Akbar AN, et al. Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Human Immunol. 2005;66:222-30.

Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol. 2005;6:353-60.

Wang HY, Wang RF. Regulatory T cells and cancer. Curr Opinion Immunol. 2007;19:217-23.

Long SA, Buckner JH. CD4+FOXP3+ T regulatory cells in human autoimmunity: more than a numbers game. J Immunol. 2011;187:2061-6.

Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TIM. Defective Suppressor Function in CD4+CD25+ T-Cells From Patients With Type 1 Diabetes. Diabetes. American Diabetes Association. 2005;54:92-9.

Walther M, Tongren JE, Andrews L, Korbel D, King E, Fletcher H, et al. Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity. 2005;23:287-96.

Lussana F, Di Ianni M, Rambaldi A. Tregs: hype or hope for allogeneic hematopoietic stem cell transplantation? Bone Marrow Transplantation. Nature Publishing Group. 2017;52:1225-32.

Ruocco MG, Chaouat G, Florez L, Bensussan A, Klatzmann D. Regulatory T-Cells in Pregnancy: Historical Perspective, State of the Art, and Burning Questions. Front Immunol. 2014;5:389.

La Rocca C, Carbone F, Longobardi S, Matarese G. The immunology of pregnancy: Regulatory T cells control maternal immune tolerance toward the fetus. Immunol Letters. 2014;162:41-8.

Liu W, Putnam AL, Xu-yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203:1701-11.

Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330-6.

Okeke EB, Uzonna JE. The Pivotal Role of Regulatory T Cells in the Regulation of Innate Immune Cells. Front Immunol. 2019;10:680.

Shevyrev D, Tereshchenko V. Treg Heterogeneity, Function, and Homeostasis. Front Immunol. 2020;10:3100.

Leber A, Teles A, Zenclussen AC. Regulatory T cells and their role in pregnancy. Am J Reprod Immunol. 2010;63:445-59.

Hayakawa S, Ohno N, Okada S, Kobayashi M. Significant augmentation of regulatory T cell numbers occurs during the early neonatal period. Clin Exp Immunol. 2017;190:268-79.

Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression — implications for anticancer therapy. Nat Rev Clin Oncol. 2019;16:356-71.

Ramlal R, Hildebrandt GC. Advances in the Use of Regulatory T-Cells for the Prevention and Therapy of Graft-vs.-Host Disease. Biomedicines. 2017;5(2):23.

Jiang TT, Chaturvedi V, Ertelt JM, Kinder JM, Clark DR, Valent AM, et al. Regulatory T cells: new keys for further unlocking the enigma of fetal tolerance and pregnancy complications. J Immunol. 2014;192:4949-56.

Guerin LR, Prins JR, Robertson SA. Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment? Hum Reprod Update. 2009;15:517-35.

Do J, Zhong F, Huang AY, Van’t Hof WJ, Finney M, Laughlin MJ. Foxp3 expression in induced T regulatory cells derived from human umbilical cord blood vs. adult peripheral blood. Bone Marrow Transplantation. Nature Publishing Group. 2018;53:1568-77.

El-Chennawi F, Rageh IM, Mansour AI, Darwish MI, Elghzaly AA, Sakr BES, et al. Comparison of the percentages of CD4 + CD25 high FOXP3 + , CD4 + CD25 low FOXP3 + , and CD4 + FOXP3 + Tregs, in the umbilical cord blood of babies born to mothers with and without preeclampsia. Am J Reprod Immunol. 2017;78:12761.

Kumar D, Xu ML. Microenvironment Cell Contribution to Lymphoma Immunity. Front Oncol. 2018;8:288.

Lundberg J, Berglund D, Molin D, Kinch A. Intratumoral expression of FoxP3-positive regulatory T-cells in T-cell lymphoma: no correlation with survival. Upsala J Med Sci. 2019;124:105-10.

Clarke SL, Betts GJ, Plant A, Wright KL, El-Shanawany TM, Harrop R, et al. CD4+CD25+FOXP3+ Regulatory T Cells Suppress Anti-Tumor Immune Responses in Patients with Colorectal Cancer. Plos one. 2006;1:129.

Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942-9.

Hus I, Bojarska-Junak A, Kamińska M, Dobrzyńska-Rutkowska A, Szatan K, Szymczyk A, et al. Imbalance in circulatory iNKT, Th17 and T regulatory cell frequencies in patients with B‑cell non‑Hodgkin’s lymphoma. Oncol Letters. 2017;14:7957-64.

Tan T, Xiang Y, Chang C, Zhou Z. Alteration of regulatory T cells in type 1 diabetes mellitus: a comprehensive review. Clin Rev Allergy Immunol. 2014;47:234-43.

Gitelman SE, Bluestone JA. Regulatory T cell therapy for type 1 diabetes: May the force be with you. J Autoimmun. 2016;71:78-87.

Dominguez-Villar M, Hafler DA. Regulatory T cells in autoimmune disease. Nat Immunol. 2018;19:665-73.

Zorn E, Kim HT, Lee SJ, Floyd BH, Litsa D, Arumugarajah S, et al. Reduced frequency of FOXP3+ CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease. Blood. 2005;106:2903-11.

Rezvani K, Mielke S, Ahmadzadeh M, Kilical Y, Savani BN, Zeilah J, et al. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood. 2006;108:1291-7.

Ukena SN, Velaga S, Geffers R, Grosse J, Baron U, Buchholz S, et al. Human regulatory T cells in allogeneic stem cell transplantation. Blood. 2011;118:82-92.

Matsuoka K, Kim HT, McDonough S, Bascug G, Warshauer B, Koreth J, et al. Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation. J Clin Invest. 2010;120:1479-93.