CD4⁺CD25^-FoxP3⁺ T cells: a distinct subset or a heterogeneous population?

References

• Sakaguchi S, Takahashi T, Nishizuka Y. Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J Exp Med. 1982;156(6):1577–1586. doi:10.1084/jem.156.6.1577.
   PubMed Web of Science ®Google Scholar
• Romano M, Fanelli G, Albany CJ, Giganti G, Lombardi G. Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity. Front Immunol. 2019;10:43. doi:10.3389/fimmu.2019.00043.
   PubMed Web of Science ®Google Scholar
• 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(7):2537–2544. doi:10.1182/blood-2007-03-082578.
   PubMed Web of Science ®Google Scholar
• Bonelli M, von Dalwigk K, Savitskaya A, Smolen JS, Scheinecker C. Foxp3 expression in CD4+ T cells of patients with systemic lupus erythematosus: a comparative phenotypic analysis. Ann Rheum Dis. 2008;67(5):664–671. doi:10.1136/ard.2007.074690.
   PubMed Web of Science ®Google Scholar
• Jafarinia M, Mehdipour F, Hosseini SV, Ghahramani L, Hosseinzadeh M, Ghaderi A. Determination of a CD4 + CD25-FoxP3+ T cells subset in tumor-draining lymph nodes of colorectal cancer secreting IL-2 and IFN-γ. Tumour Biol. 2016;37(11):14659–14666. doi:10.1007/s13277-016-5345-y.
   PubMedGoogle Scholar
• WanJun C, Wenwen J, Hardegen N, et al. Conversion of peripheral CD CD25 naive T cells to CD4 CD25 regulatory T cells by TGF-induction of transcription factor foxp3. J Exp Med. 2003;198:1875–1886. doi:10.1084/jem.20030152.
   PubMed Web of Science ®Google Scholar
• Coleman MM, Finlay CM, Moran B, Keane J, Dunne PJ, Mills KH. The immunoregulatory role of CD4⁺ FoxP3⁺ CD25⁻ regulatory T cells in lungs of mice infected with Bordetella pertussis. FEMS Immunol Med Microbiol. 2012;64(3):413–424. doi:10.1111/j.1574-695X.2011.00927.x.
   PubMed Web of Science ®Google Scholar
• Yang HX, Zhang W, Zhao LD, et al. Are CD4 + CD25-Foxp3+ cells in untreated new-onset lupus patients regulatory T cells? Arthritis Res Ther. 2009;11(5):R153. doi:10.1186/ar2829.
   PubMed Web of Science ®Google Scholar
• Schmidl C, Delacher M, Huehn J, Feuerer M. Epigenetic mechanisms regulating T-cell responses. J Allergy Clin Immunol. 2018;142(3):728–743. doi:10.1016/j.jaci.2018.07.014.
   PubMed Web of Science ®Google Scholar
• Luckheeram RV, Zhou R, Verma AD, Xia B. CD4⁺T cells: differentiation and functions. Clin Dev Immunol. 2012;2012:9251352012.10.1155/2012/925135 doi:10.1155/2012/925135.
   PubMedGoogle Scholar
• Murphy KM, Stockinger B. Effector T cell plasticity: flexibility in the face of changing circumstances. Nat Immunol. 2010;11(8):674–680. doi:10.1038/ni.1899.
   PubMed Web of Science ®Google Scholar
• Miyara M, Yoshioka Y, Kitoh A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899–911. doi:10.1016/j.immuni.2009.03.019.
   PubMed Web of Science ®Google Scholar
• Seddiki N, Santner-Nanan B, Martinson J, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203(7):1693–1700. doi:10.1084/jem.20060468.
   PubMed Web of Science ®Google Scholar
• Miyara M, Gorochov G, Ehrenstein M, Musset L, Sakaguchi S, Amoura Z. Human FoxP3+ regulatory T cells in systemic autoimmune diseases. Autoimmun Rev. 2011;10(12):744–755. doi:10.1016/j.autrev.2011.05.004.
   PubMed Web of Science ®Google Scholar
• Sakaguchi S, Wing K, Miyara M. Regulatory T cells–a brief history and perspective. Eur J Immunol. 2007;37(S1):S116–S23. doi:10.1002/eji.200737593.
   PubMedGoogle Scholar
• Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity. 2004;21(2):267–277. doi:10.1016/j.immuni.2004.07.009.
   PubMed Web of Science ®Google Scholar
• Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–1061. doi:10.1126/science.1079490.
   PubMed Web of Science ®Google Scholar
• Shevyrev D, Tereshchenko V. Treg heterogeneity, function, and homeostasis. Front Immunol. 2019;10:3100doi:10.3389/fimmu.2019.03100.
   PubMed Web of Science ®Google Scholar
• Tao R, de Zoeten EF, Ozkaynak E, et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med. 2007;13(11):1299–1307. doi:10.1038/nm1652.
   PubMed Web of Science ®Google Scholar
• Thornton AM, Korty PE, Tran DQ, et al. Expression of helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. JI. 2010;184(7):3433–3441. doi:10.4049/jimmunol.0904028.
   Google Scholar
• Ronchetti S, Ricci E, Petrillo MG, et al. Glucocorticoid-induced tumour necrosis factor receptor-related protein: a key marker of functional regulatory T cells. Journal of Immunology Research. 2015;2015:1–17. 2015 doi:10.1155/2015/171520.
   Web of Science ®Google Scholar
• Ohkura N, Hamaguchi M, Morikawa H, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012;37(5):785–799. doi:10.1016/j.immuni.2012.09.010.
   PubMed Web of Science ®Google Scholar
• Minskaia E, Saraiva BC, Soares MMV, et al. Molecular markers distinguishing T cell subtypes with TSDR strand-bias methylation. Front Immunol. 2018;9:2540doi:10.3389/fimmu.2018.02540.
   PubMed Web of Science ®Google Scholar
• Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4 + CD25high regulatory cells in human peripheral blood. J Immunol. 2001;167(3):1245–1253. doi:10.4049/jimmunol.167.3.1245.
   PubMed Web of Science ®Google Scholar
• Kanamori M, Nakatsukasa H, Okada M, Lu Q, Yoshimura A. Induced regulatory T cells: their development, stability, and applications. Trends Immunol. 2016;37(11):803–811. doi:10.1016/j.it.2016.08.012.
   PubMed Web of Science ®Google Scholar
• Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. 2005;6(12):1219–1227. doi:10.1038/ni1265.
   PubMed Web of Science ®Google Scholar
• de Lafaille MAC, Lafaille J. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?. Immunity. 2009;30(5):626–635. doi:10.1016/j.immuni.2009.05.002.
   PubMed Web of Science ®Google Scholar
• Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol. 2003;3(3):253–257. 10.1038/nri1032 doi:10.1038/nri1032.
   PubMed Web of Science ®Google Scholar
• Malek TR. The biology of interleukin-2. Annu Rev Immunol. 2008;26:453–479. 10.1146/annurev.immunol.26.021607.090357 doi:10.1146/annurev.immunol.26.021607.090357.
   PubMed Web of Science ®Google Scholar
• Flynn MJ, Hartley JA. The emerging role of anti-CD25 directed therapies as both immune modulators and targeted agents in cancer. Br J Haematol. 2017;179(1):20–35. doi:10.1111/bjh.14770.
   PubMed Web of Science ®Google Scholar
• Fan MY, Low JS, Tanimine N, et al. Differential roles of IL-2 signaling in developing versus mature tregs. Cell Rep. 2018;25(5):1204–1213. e4 doi:10.1016/j.celrep.2018.10.002.
   PubMed Web of Science ®Google Scholar
• Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med. 2005;201(5):723–735. doi:10.1084/jem.20041982.
   PubMed Web of Science ®Google Scholar
• Toomer KH, Malek TR. Conditional deletion of CD25 in Tregs abrogates their suppressive function independently of Foxp3. J Immunol. 2018;200(1 Supplement):101.6.
   Web of Science ®Google Scholar
• Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity. 1995;3(4):521–530. doi:10.1016/1074-7613(95)90180-9.
   PubMed Web of Science ®Google Scholar
• De Herve M-g, Gonzales E, Hendel-Chavez H, et al. CD25 appears non essential for human peripheral T(reg) maintenance in vivo. PloS One. 2010;5(7):e11784doi:10.1371/journal.pone.0011784.
   PubMed Web of Science ®Google Scholar
• Vondran FW, Timrott K, Tross J, et al. Impact of Basiliximab on regulatory T-cells early after kidney transplantation: down-regulation of CD25 by receptor modulation. Transpl Int. 2010;23(5):514–523. doi:10.1111/j.1432-2277.2009.01013.x.
   PubMed Web of Science ®Google Scholar
• Liu W, Putnam AL, Xu-Yu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203(7):1701–1711. doi:10.1084/jem.20060772.
   PubMed Web of Science ®Google Scholar
• Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM. Attenuation of CD8(+) T-cell function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin's lymphoma. Cancer Res. 2006;66(20):10145–10152. doi:10.1158/0008-5472.CAN-06-1822.
   PubMed Web of Science ®Google Scholar
• Lin SC, Chen KH, Lin CH, Kuo CC, Ling QD, Chan CH. The quantitative analysis of peripheral blood FOXP3-expressing T cells in systemic lupus erythematosus and rheumatoid arthritis patients. Eur J Clin Invest. 2007;37(12):987–996. doi:10.1111/j.1365-2362.2007.01882.x.
   PubMed Web of Science ®Google Scholar
• Suárez A, de Paz B, Prado C, et al. Effects of glucocorticoid treatment on CD25⁻FOXP3⁺ population and cytokine-producing cells in rheumatoid arthritis. Rheumatology (Oxford)). 2012;51(7):1198–1207.
   PubMed Web of Science ®Google Scholar
• Wu JH, Zhou M, Jin Y, et al. Generation and immune regulation of CD4 + CD25-Foxp3+ T cells in chronic obstructive pulmonary disease. Front Immunol. 2019;10:220doi:10.3389/fimmu.2019.00220.
   PubMed Web of Science ®Google Scholar
• Zóka A, Barna G, Somogyi A, et al. Extension of the CD4⁺Foxp3⁺CD25(-/low) regulatory T-cell subpopulation in type 1 diabetes mellitus. Autoimmunity. 2015;48(5):289–297. doi:10.3109/08916934.2014.992518.
   PubMed Web of Science ®Google Scholar
• Angerami MT, Suarez GV, Vecchione MB, et al. Expansion of CD25-negative forkhead Box P3-positive T cells during HIV and Mycobacterium tuberculosis infection. Front Immunol. 2017;8:528doi:10.3389/fimmu.2017.00528.
   PubMed Web of Science ®Google Scholar
• Hu X, Gu Y, Zhao S, Hua S, Jiang Y. Elevated circulating CD4 + CD25-Foxp3+ regulatory T cells in patients with nonsmall cell lung cancer. Cancer Biother Radiopharm. 2019;34(5):325–333. doi:10.1089/cbr.2018.2672.
   PubMed Web of Science ®Google Scholar
• Faghih Z, Erfani N, Haghshenas MR, Safaei A, Talei AR, Ghaderi A. Immune profiles of CD4+ lymphocyte subsets in breast cancer tumor draining lymph nodes. Immunol Lett. 2014;158(1-2):57–65. 10.1016/j.imlet.2013.11.021 doi:10.1016/j.imlet.2013.11.021.
   PubMed Web of Science ®Google Scholar
• Allan SE, Crome SQ, Crellin NK, et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol. 2007;19(4):345–354. doi:10.1093/intimm/dxm014.
   PubMed Web of Science ®Google Scholar
• Zhang B, Zhang X, Tang F, Zhu L, Liu Y, Lipsky P. Clinical significance of increased CD4+ CD25− Foxp3+ T cells in patients with new-onset systemic lupus erythematosus. Ann Rheum Dis. 2008;67(7):1037–1040. doi:10.1136/ard.2007.083543.
   PubMed Web of Science ®Google Scholar
• Bonelli M, Savitskaya A, Steiner CW, Rath E, Smolen JS, Scheinecker C. Phenotypic and functional analysis of CD4+ CD25- Foxp3+ T cells in patients with systemic lupus erythematosus. J Immunol. 2009;182(3):1689–1695. doi:10.4049/jimmunol.182.3.1689.
   PubMed Web of Science ®Google Scholar
• Suen JL, Li HT, Jong YJ, Chiang BL, Yen JH. Altered homeostasis of CD4(+) FoxP3(+) regulatory T-cell subpopulations in systemic lupus erythematosus. Immunology. 2009;127(2):196–205. doi:10.1111/j.1365-2567.2008.02937.x.
   PubMed Web of Science ®Google Scholar
• Bonelli M, Göschl L, Blüml S, et al. CD4+ CD25-Foxp3+ T cells: a marker for lupus nephritis? Arthritis Res Ther. 2014;16(2):R104. doi:10.1186/ar4553.
   PubMed Web of Science ®Google Scholar
• Ferreira RC, Simons HZ, Thompson WS, et al. Cells with Treg-specific FOXP3 demethylation but low CD25 are prevalent in autoimmunity. J Autoimmun. 2017;84:75–86. doi:10.1016/j.jaut.2017.07.009.
   PubMed Web of Science ®Google Scholar
• El-Maraghy N, Ghaly MS, Dessouki O, Nasef SI, Metwally L. CD4+ CD25-Foxp3+ T cells as a marker of disease activity and organ damage in systemic lupus erythematosus patients. aoms. 2018;14(5):1033–1040. doi:10.5114/aoms.2016.63597.
   Google Scholar
• Niakan A, Faghih Z, Talei AR, Ghaderi A. Cytokine profile of CD4 + CD25-FoxP3+ T cells in tumor-draining lymph nodes from patients with breast cancer . Mol Immunol. 2019;116:90–97. doi:10.1016/j.molimm.2019.10.007.
   PubMed Web of Science ®Google Scholar
• Fakhimi M, Talei AR, Ghaderi A, Habibagahi M, Helios RM. CD73 and CD39 Induction in regulatory T cells exposed to adipose derived Mesenchymal Stem. Cells Cell J. 2020;22(2):236–244. doi:10.22074/cellj.2020.6313.
   Google Scholar
• Nishioka T, Shimizu J, Iida R, Yamazaki S, Sakaguchi S. CD4 + CD25 + Foxp3+ T cells and CD4 + CD25-Foxp3+ T cells in aged mice. J Immunol. 2006;176(11):6586–6593. doi:10.4049/jimmunol.176.11.6586.
   PubMed Web of Science ®Google Scholar
• Mantel PY, Ouaked N, Ruckert B, et al. Molecular mechanisms underlying FOXP3 induction in human T cells. J Immunol. 2006;176(6):3593–3602. doi:10.4049/jimmunol.176.6.3593.
   PubMed Web of Science ®Google Scholar
• Xiao S, Matsui K, Fine A, et al. FasL promoter activation by IL‐2 through SP1 and NFAT but not Egr‐2 and Egr‐3. Eur J Immunol. 1999;29(11):3456–3465. doi:10.1002/(SICI)1521-4141(199911)29:11 < 3456::AID-IMMU3456 > 3.0.CO;2-B.
   PubMed Web of Science ®Google Scholar
• Kim YC, Bhairavabhotla R, Yoon J, et al. Oligodeoxynucleotides stabilize Helios-expressing Foxp3+ human T regulatory cells during in vitro expansion. Blood. 2012;119(12):2810–2818. doi:10.1182/blood-2011-09-377895.
   PubMed Web of Science ®Google Scholar
• Golding A, Hasni S, Illei G, Shevach EM. The percentage of FoxP3 + Helios + Treg cells correlates positively with disease activity in systemic lupus erythematosus. Arthritis Rheum. 2013;65(11):2898–2906. doi:10.1002/art.38119.
   PubMedGoogle Scholar
• Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6(11):1142–1151. doi:10.1038/ni1263.
   PubMed Web of Science ®Google Scholar
• Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239–245. doi:10.1038/ni1443.
   PubMed Web of Science ®Google Scholar
• Franceschini D, Paroli M, Francavilla V, et al. PD-L1 negatively regulates CD4 + CD25 + Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Invest. 2009;119(3):551–564. doi:10.1172/JCI36604.
   PubMed Web of Science ®Google Scholar
• Miyao T, Floess S, Setoguchi R, et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity. 2012;36(2):262–275. doi:10.1016/j.immuni.2011.12.012.
   PubMed Web of Science ®Google Scholar
• Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev. 2008;224(1):166–182. doi:10.1111/j.1600-065X.2008.00662.x.
   PubMedGoogle Scholar
• Long SA, Cerosaletti K, Bollyky PL, et al. Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4(+)CD25(+) regulatory T-cells of type 1 diabetic subjects. Diabetes. 2010;59(2):407–415. doi:10.2337/db09-0694.
   PubMed Web of Science ®Google Scholar
• Nishimura E, Sakihama T, Setoguchi R, Tanaka K, Sakaguchi S. Induction of antigen-specific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3 + CD25 + CD4+ regulatory T cells. Int Immunol. 2004;16(8):1189–1201. doi:10.1093/intimm/dxh122.
   PubMed Web of Science ®Google Scholar
• Elkord E. Helios should not be cited as a marker of human thymus-derived tregs. Commentary: Helios(+) and Helios(-) cells coexist within the natural FOXP3(+) T regulatory cell subset in humans. Front Immunol. 2016;7:276. doi:10.3389/fimmu.2016.00276.
   PubMed Web of Science ®Google Scholar
• Furtado GC, Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ. Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med. 2002;196(6):851–857. doi:10.1084/jem.20020190.
   PubMed Web of Science ®Google Scholar
• Gavin MA, Clarke SR, Negrou E, Gallegos A, Rudensky A. Homeostasis and anergy of CD4(+)CD25(+) suppressor T cells in vivo. Nat Immunol. 2002;3(1):33–41. doi:10.1038/ni743.
   PubMed Web of Science ®Google Scholar
• Laurence A, O'Shea JJ. T(H)-17 differentiation: of mice and men. Nat Immunol. 2007;8(9):903–905. doi:10.1038/ni0907-903.
   PubMed Web of Science ®Google Scholar
• Zelenay S, Lopes-Carvalho T, Caramalho I, Moraes-Fontes MF, Rebelo M, Demengeot J. Foxp3+ CD25- CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion. Proc Natl Acad Sci Usa. 2005;102(11):4091–4096. doi:10.1073/pnas.0408679102.
   PubMed Web of Science ®Google Scholar
• Ono M, Shimizu J, Miyachi Y, Sakaguchi S. Control of autoimmune myocarditis and multiorgan inflammation by glucocorticoid-induced TNF receptor family-related protein(high), Foxp3-expressing CD25+ and CD25- regulatory T cells. J Immunol. 2006;176(8):4748–4756. doi:10.4049/jimmunol.176.8.4748.
   PubMed Web of Science ®Google Scholar
• Wang J, Ioan-Facsinay A, van der Voort EI, Huizinga TW, Toes RE. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol. 2007;37(1):129–138. doi:10.1002/eji.200636435.
   PubMed Web of Science ®Google Scholar
• Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4 + CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330–336. 10.1038/ni904 doi:10.1038/ni904.
   PubMed Web of Science ®Google Scholar
• O'Gorman WE, Dooms H, Thorne SH, et al. The initial phase of an immune response functions to activate regulatory T cells. J Immunol. 2009;183(1):332–339. doi:10.4049/jimmunol.0900691.
   PubMed Web of Science ®Google Scholar
• Chavele KM, Ehrenstein MR. Regulatory T-cells in systemic lupus erythematosus and rheumatoid arthritis. FEBS Lett. 2011;585(23):3603–3610. doi:10.1016/j.febslet.2011.07.043.
   PubMed Web of Science ®Google Scholar
• Pillai V, Ortega SB, Wang C, Karandikar N. Transient regulatory T-cells: a state attained by all activated human T-cells. Clin Immunol. 2007;123(1):18–29. doi:10.1016/j.clim.2006.10.014.
   PubMed Web of Science ®Google Scholar
• Walker MR, Kasprowicz DJ, Gersuk VH, et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+ CD25–T cells. J Clin Invest. 2003;112(9):1437–1443. doi:10.1172/JCI200319441.
   PubMed Web of Science ®Google Scholar
• Rech AJ, Mick R, Martin S, et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med. 2012;4(134):134. ra62.10.1126/scitranslmed.3003330
   Web of Science ®Google Scholar
• Horwitz DA. Identity of mysterious CD4 + CD25-Foxp3+ cells in SLE . Arthritis Res Ther. 2010;12(1):101doi:10.1186/ar2894.
   PubMed Web of Science ®Google Scholar
• Sharfe N, Dadi HK, Shahar M, Roifman CM. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci USA. 1997;94(7):3168–3171. doi:10.1073/pnas.94.7.3168.
   PubMed Web of Science ®Google Scholar
• Jamee M, Zaki-Dizaji M, Lo B, et al. Clinical, immunological, and genetic features in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-like syndrome. The Journal of Allergy and Clinical Immunology: In Practice. 2020. doi:10.1016/j.jaip.2020.04.070.
   PubMed Web of Science ®Google Scholar
• Vignoli M, Ciullini Mannurita S, Fioravanti A, et al. CD25 deficiency: a new conformational mutation prevents the receptor expression on cell surface. Clin Immunol. 2019;201:15–19. doi:10.1016/j.clim.2019.02.003.
   PubMed Web of Science ®Google Scholar
• Al Sukaiti N, Al Sinani A, Al Ismaily S, Shaikh S, Al Abrawi S. Pulmonary hemorrhage in a case of CD25 deficiency. LymphoSign Journal. 2014;01 (01):39–43. doi:10.14785/lpsn-2014-0003.
   Google Scholar
• Bezrodnik L, Caldirola MS, Seminario AG, Moreira I, Gaillard MI. Follicular bronchiolitis as phenotype associated with CD25 deficiency. Clin Exp Immunol. 2014;175(2):227–234. doi:10.1111/cei.12214.
   PubMed Web of Science ®Google Scholar
• Goudy K, Aydin D, Barzaghi F, et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol. 2013;146(3):248–261. doi:10.1016/j.clim.2013.01.004.
   PubMed Web of Science ®Google Scholar
• Roth TL, Puig-Saus C, Yu R, et al. Reprogramming human T cell function and specificity with non-viral genome targeting. Nature. 2018;559(7714):405–409. doi:10.1038/s41586-018-0326-5.
   PubMed Web of Science ®Google Scholar
• Caudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol. 2007;119(2):482–487. doi:10.1016/j.jaci.2006.10.007
   PubMed Web of Science ®Google Scholar
• Davidson TS, DiPaolo RJ, Andersson J, Shevach EM. Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J Immunol. 2007;178(7):4022–4026. 10.4049/jimmunol.178.7.4022 doi:10.4049/jimmunol.178.7.4022.
   PubMed Web of Science ®Google Scholar
• Verbsky JW, Chatila TA. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr Opin Pediatr. 2013;25(6):708–714. doi:10.1097/MOP.0000000000000029.
   PubMed Web of Science ®Google Scholar