T Regulatory Cell Biology in Health and Disease

  • Fayhan J. Alroqi
  • Talal A. ChatilaEmail author
Immune Deficiency and Dysregulation (DP Huston and C Kuo, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Immune Deficiency and Dysregulation


Regulatory T (Treg) cells that express the transcription factor forkhead box protein P3 (FOXP3) play an essential role in enforcing immune tolerance to self tissues, regulating host-commensal flora interaction, and facilitating tissue repair. Their deficiency and/or dysfunction trigger unbridled autoimmunity and inflammation. A growing number of monogenic defects have been recognized that adversely impact Treg cell development, differentiation, and/or function, leading to heritable diseases of immune dysregulation and autoimmunity. In this article, we review recent insights into Treg cell biology and function, with particular attention to lessons learned from newly recognized clinical disorders of Treg cell deficiency.


Regulatory T (Treg) cell T conventional cell (Tconv) Immune dysregulation Autoimmunity IPEX IPEX like 


Compliance with Ethical Standards

Conflict of Interest

Talal Chatila and Fayhan Alroqi declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Sleckman BP, Gorman JR, Alt FW. Accessibility control of antigen-receptor variable-region gene assembly: role of cis-acting elements. Annu Rev Immunol. 1996;14:459–81.CrossRefPubMedGoogle Scholar
  2. 2.
    Laufer TM, Fan L, Glimcher LH. Self-reactive T cells selected on thymic cortical epithelium are polyclonal and are pathogenic in vivo. J Immunol. 1999;162(9):5078–84.PubMedGoogle Scholar
  3. 3.
    Peterson P et al. APECED: a monogenic autoimmune disease providing new clues to self-tolerance. Immunol Today. 1998;19(9):384–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Ohashi PS. Negative selection and autoimmunity. Curr Opin Immunol. 2003;15(6):668–76.CrossRefPubMedGoogle Scholar
  5. 5.
    Lio CW, Hsieh CS. Becoming self-aware: the thymic education of regulatory T cells. Curr Opin Immunol. 2011;23(2):213–9.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Klein L, Jovanovic K. Regulatory T cell lineage commitment in the thymus. Semin Immunol. 2011;23(6):401–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Bonomo A et al. Pathogenesis of post-thymectomy autoimmunity. Role of syngeneic MLR-reactive T cells. J Immunol. 1995;154(12):6602–11.PubMedGoogle Scholar
  8. 8.
    Asano M et al. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med. 1996;184(2):387–96.CrossRefPubMedGoogle Scholar
  9. 9.
    Sakaguchi S et al. 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. 1995;155(3):1151–64.PubMedGoogle Scholar
  10. 10.
    Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4 + CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61.CrossRefPubMedGoogle Scholar
  12. 12.
    Zheng Y, Rudensky AY. Foxp3 in control of the regulatory T cell lineage. Nat Immunol. 2007;8(5):457–62.CrossRefPubMedGoogle Scholar
  13. 13.
    Bennett CL et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20–1.CrossRefPubMedGoogle Scholar
  14. 14.
    Clark LB et al. Cellular and molecular characterization of the scurfy mouse mutant. J Immunol. 1999;162(5):2546–54.PubMedGoogle Scholar
  15. 15.
    Komatsu N et al. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci U S A. 2009;106(6):1903–8.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Abbas AK et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol. 2013;14(4):307–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Maynard CL et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3− precursor cells in the absence of interleukin 10. Nat Immunol. 2007;8(9):931–41.CrossRefPubMedGoogle Scholar
  18. 18.
    Gutcher I et al. Autocrine transforming growth factor-beta1 promotes in vivo Th17 cell differentiation. Immunity. 2011;34(3):396–408.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Takahashi T et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192(2):303–10.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    McHugh RS et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity. 2002;16(2):311–23.CrossRefPubMedGoogle Scholar
  21. 21.
    Miyara M et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899–911.CrossRefPubMedGoogle Scholar
  22. 22.
    Himmel ME et al. Helios+ and Helios− cells coexist within the natural FOXP3+ T regulatory cell subset in humans. J Immunol. 2013;190(5):2001–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Yadav M et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med. 2012;209(10):1713–22. S1-19.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Zhou X et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol. 2009;10(9):1000–7.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.•
    Komatsu N et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014;20(1):62–8. This article shows production of pathogenic TH17 cells due to Foxp3 instability and their contribution to the pathogenesis of autoimmunity.CrossRefPubMedGoogle Scholar
  26. 26.
    Sawant DV, Vignali DA. Once a Treg, always a Treg? Immunol Rev. 2014;259(1):173–91.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Jordan MS et al. Thymic selection of CD4 + CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol. 2001;2(4):301–6.CrossRefPubMedGoogle Scholar
  28. 28.•
    Mahmud SA et al. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat Immunol. 2014;15(5):473–81. This study delineates the importance of the high expression of GITR, OX40, and TNFR2 on Treg cell progenitors to undergo successful maturation.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Tai X et al. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol. 2005;6(2):152–62.CrossRefPubMedGoogle Scholar
  30. 30.
    Hsieh CS, Lee HM, Lio CW. Selection of regulatory T cells in the thymus. Nat Rev Immunol. 2012;12(3):157–67.PubMedGoogle Scholar
  31. 31.
    Gavin MA et al. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci U S A. 2006;103(17):6659–64.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Floess S et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 2007;5(2), e38.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lal G et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol. 2009;182(1):259–73.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ohkura N 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):785–99.CrossRefPubMedGoogle Scholar
  35. 35.•
    Kitagawa Y, Wing JB, Sakaguchi S. Transcriptional and epigenetic control of regulatory T cell development. Prog Mol Biol Transl Sci. 2015;136:1–33. This publication discusses key transcriptional and epigenetic factors that are important for Treg cell genetic profile.CrossRefPubMedGoogle Scholar
  36. 36.•
    Kim HJ et al. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science. 2015;350(6258):334–9. This experimental study provides evidence that Helios is important factor in Treg cell suppressive activity.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Wohlfert EA et al. GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J Clin Invest. 2011;121(11):4503–15.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wang Y, Su MA, Wan YY. An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity. 2011;35(3):337–48.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.••
    Charbonnier LM et al. Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling. Nat Immunol. 2015;16(11):1162–73. This publication shows the critical role for Notch signaling in controlling peripheral Treg cell function.CrossRefPubMedGoogle Scholar
  40. 40.
    Bilate AM, Lafaille JJ. Induced CD4 + Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol. 2012;30:733–58.CrossRefPubMedGoogle Scholar
  41. 41.
    Chen W et al. Conversion of peripheral CD4+ CD25− naive T cells to CD4+ CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198(12):1875–86.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Coombes JL et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007;204(8):1757–64.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Sun CM et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007;204(8):1775–85.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Haribhai D et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity. 2011;35(1):109–22.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Lathrop SK et al. Peripheral education of the immune system by colonic commensal microbiota. Nature. 2011;478(7368):250–4.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.•
    Wang S et al. MyD88 adaptor-dependent microbial sensing by regulatory T cells promotes mucosal tolerance and enforces commensalism. Immunity. 2015;43(2):289–303. This study demonstrates the important role for MyD88-dependent microbial sensing by Treg cells in promoting immunological tolerance by anti-microbial IgA responses.CrossRefPubMedGoogle Scholar
  47. 47.•
    Kawamoto S et al. Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity. 2014;41(1):152–65. This article reviews the contribution of Foxp3 + T cells in diversification of gut microbiota.Google Scholar
  48. 48.•
    Pandiyan P, Zhu J. Origin and functions of pro-inflammatory cytokine producing Foxp3+ regulatory T cells. Cytokine. 2015;76(1):13–24. This study reviews the mechanisms of induction of effector cytokines in Foxp3 + Treg cells.Google Scholar
  49. 49.•
    Noval Rivas M et al. Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity. 2015;42(3):512–23. Study shows reprogramming of Treg cells into Th2-like cells under the action of IL-4R signaling. Interruption of this process might provide candidate therapeutic strategies in food allergy.CrossRefPubMedGoogle Scholar
  50. 50.
    Wing K et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–5.CrossRefPubMedGoogle Scholar
  51. 51.
    Huang CT et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21(4):503–13.CrossRefPubMedGoogle Scholar
  52. 52.
    Garin MI et al. Galectin-1: a key effector of regulation mediated by CD4 + CD25+ T cells. Blood. 2007;109(5):2058–65.CrossRefPubMedGoogle Scholar
  53. 53.
    Grossman WJ et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity. 2004;21(4):589–601.CrossRefPubMedGoogle Scholar
  54. 54.
    Pandiyan P et al. CD4 + CD25 + Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol. 2007;8(12):1353–62.CrossRefPubMedGoogle Scholar
  55. 55.
    Collison LW et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450(7169):566–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Li MO et al. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146.CrossRefPubMedGoogle Scholar
  57. 57.
    Koch MA et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol. 2009;10(6):595–602.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Zheng Y et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature. 2009;458(7236):351–6.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Chaudhry A et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science. 2009;326(5955):986–91.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Chung Y et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011;17(8):983–8.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Rouse BT, Sarangi PP, Suvas S. Regulatory T cells in virus infections. Immunol Rev. 2006;212:272–86.CrossRefPubMedGoogle Scholar
  62. 62.••
    Arpaia N et al. A distinct function of regulatory T cells in tissue protection. Cell. 2015;162(5):1078–89. This providing a new role for Treg cells in tissue protection.CrossRefPubMedGoogle Scholar
  63. 63.
    Fyhrquist N et al. Foxp3+ cells control Th2 responses in a murine model of atopic dermatitis. J Investig Dermatol. 2012;132(6):1672–80.CrossRefPubMedGoogle Scholar
  64. 64.
    Vudattu NK, Herold KC. Delayed anti-CD3 therapy in a mouse heart transplant model induced tolerance and long-term survival of allograft: achieving tolerance. Immunotherapy. 2013;5(11):1173–6.CrossRefPubMedGoogle Scholar
  65. 65.
    Ait-Oufella H et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med. 2006;12(2):178–80.CrossRefPubMedGoogle Scholar
  66. 66.
    Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol. 2007;120(4):744–50. quiz 751–2.CrossRefPubMedGoogle Scholar
  67. 67.
    Gambineri E et al. Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity. J Allergy Clin Immunol. 2008;122(6):1105–12. e1.CrossRefPubMedGoogle Scholar
  68. 68.•
    Kucuk ZY, et al. A challenging undertaking: Stem cell transplantation for immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. J Allergy Clin Immunol. 2015. doi: 10.1016/j.jaci.2015.09.030. This publication highlights HSCT long-term outcomes in patients with IPEX syndrome.
  69. 69.
    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):708–14.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Sadlack B et al. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur J Immunol. 1995;25(11):3053–9.CrossRefPubMedGoogle Scholar
  71. 71.
    Sadlack B et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. 1993;75(2):253–61.CrossRefPubMedGoogle Scholar
  72. 72.
    Suzuki H et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science. 1995;268(5216):1472–6.CrossRefPubMedGoogle Scholar
  73. 73.
    Snow JW et al. Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice. J Immunol. 2003;171(10):5042–50.CrossRefPubMedGoogle Scholar
  74. 74.
    Sharfe N et al. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci U S A. 1997;94(7):3168–71.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Caudy AA et al. 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):482–7.CrossRefPubMedGoogle Scholar
  76. 76.
    Goudy K et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol. 2013;146(3):248–61.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Bezrodnik L et al. Follicular bronchiolitis as phenotype associated with CD25 deficiency. Clin Exp Immunol. 2014;175(2):227–34.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Fontenot JD et al. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6(11):1142–51.CrossRefPubMedGoogle Scholar
  79. 79.
    Barron L et al. Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. J Immunol. 2010;185(11):6426–30.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Maloy KJ, Powrie F. Fueling regulation: IL-2 keeps CD4+ Treg cells fit. Nat Immunol. 2005;6(11):1071–2.CrossRefPubMedGoogle Scholar
  81. 81.
    Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature. 2006;441(7095):890–3.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Pipkin ME et al. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity. 2010;32(1):79–90.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Felices M et al. Functional NK cell repertoires are maintained through IL-2R alpha and Fas ligand. J Immunol. 2014;192(8):3889–97.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Cui Y et al. Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol Cell Biol. 2004;24(18):8037–47.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Bernasconi A et al. Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics. 2006;118(5):e1584–92.CrossRefPubMedGoogle Scholar
  86. 86.
    Nadeau K, Hwa V, Rosenfeld RG. STAT5b deficiency: an unsuspected cause of growth failure, immunodeficiency, and severe pulmonary disease. J Pediatr. 2011;158(5):701–8.CrossRefPubMedGoogle Scholar
  87. 87.
    Bezrodnik L et al. Long-term follow-up of STAT5B deficiency in three argentinian patients: clinical and immunological features. J Clin Immunol. 2015;35(3):264–72.CrossRefPubMedGoogle Scholar
  88. 88.
    Kofoed EM et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. 2003;349(12):1139–47.CrossRefPubMedGoogle Scholar
  89. 89.
    Qureshi OS et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332(6029):600–3.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.••
    Lo B et al. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436–40. It is providing a mechanistic view of LRBA in controlling CTLA4 expression and highlighting response to Abetacept in LRBA deficient patients.CrossRefPubMedGoogle Scholar
  91. 91.••
    Charbonnier LM et al. Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J Allergy Clin Immunol. 2015;135(1):217–27. Study shows increased TFH and decreased TFR cell in LRBA-deficient patients and their implication in the development of autoantibodies.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.••
    Kuehn HS et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204):1623–7. This article demonstrates that CTLA4 haploinsufficiency in human might present with IPEX like phenotype.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.••
    Schubert D et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410–6. This study reported a spectrum of genetic alterations leading to defective CTLA-4 function.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Lopez-Herrera G et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet. 2012;90(6):986–1001.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Alangari A et al. LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. J Allergy Clin Immunol. 2012;130(2):481–8. e2.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Serwas NK et al. Atypical manifestation of LRBA deficiency with predominant IBD-like phenotype. Inflamm Bowel Dis. 2015;21(1):40–7.CrossRefPubMedGoogle Scholar
  97. 97.•
    Revel-Vilk S et al. Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation. Clin Immunol. 2015;159(1):84–92. This study emphasizes that LRBA deficiency should be considered in patients presenting with ALPS like phenotype.CrossRefPubMedGoogle Scholar
  98. 98.••
    Lee S, et al. Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4. J Allergy Clin Immunol. 2015. This article shows the positive effect of abatacept in CTLA4 haploinsuuficiency.Google Scholar
  99. 99.
    Seidel MG et al. Long-term remission after allogeneic hematopoietic stem cell transplantation in LPS-responsive beige-like anchor (LRBA) deficiency. J Allergy Clin Immunol. 2015;135(5):1384–90 e1-8.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Division of ImmunologyBoston Children’s HospitalBostonUSA
  2. 2.Department of PediatricsHarvard Medical SchoolBostonUSA

Personalised recommendations