Immune Regulation in Human Health and Disease

Abstract

The immune system requires a homeostatic equilibrium among the mechanisms that assure self‐tolerance, those that control the capacity to mount life‐long immunity to pathogenic microbes and those that attenuate effector mechanisms from inducing immune pathology. There are multiple processes in place to ensure that healthy immune regulation and FOXP3+ T regulatory (Treg) cells are thought to be the major players. Treg cells exercise their regulatory role through various contact‐dependent and ‐independent mechanisms, and FOXP3 is the master regulator of their various functions such as inhibiting T effector (Teff) cell proliferation and inflammatory cytokine production. Various autoimmune diseases such as IPEX occur when Treg‐cell function or numbers are abrogated. Although there is evidence that supports the involvement of Treg cells in the development of autoimmune disease, there are inconsistencies in the literature owing to the lack of Treg‐cell‐specific markers.

Key Concepts

  • The immune system employs multiple tolerance mechanisms to maintain immune homeostasis.
  • Multiple specialised regulatory cells exist, FOXP3+ T regulatory (Treg) cells being one of the major players in the maintenance of immune tolerance.
  • FOXP3 is the master transcription factor of Treg cells, controlling Treg‐cell phenotype and suppressive functions.
  • Autoimmune diseases such as IPEX arise when Treg cells are defective or lacking, which can be due to mutations at the Foxp3 gene locus.
  • Multiple markers are currently being used to study the Treg‐cell population; however, these markers are not specific to Treg cells and therefore are the cause of inconsistencies in the literature on the topic of Treg‐cell function in health and disease.
  • Disturbances in FOXP3+ Treg‐cell development, homeostasis and/or function are thought to occur in many autoimmune and chronic inflammatory diseases in humans.

Keywords: immunoregulation; immune tolerance; Treg; FOXP3; IPEX

Figure 1. Mechanisms of Treg‐cell‐suppressive function. Treg cells employ multiple mechanisms to exert their suppressive effects. (1) Treg cells secrete inhibitory cytokines: IL‐10, TGF‐β and IL‐35. (2) Treg cells mediate metabolic disruption using up IL‐2, hydrolysing ATP (adenosine triphosphate) to adenosine, which is a potent inhibitory molecule, and transferring cAMP (cyclic adenosine monophosphate) to Teff cells through gap junctions. (3) Mechanisms targeting dendritic cells include binding of CTLA‐4 on Treg cells to CD80/CD86 on DCs (dendritic cells), inhibiting DC‐mediated Teff‐cell activation. LAG‐3 on Treg cells binds MHC II on DCs inhibiting their function. (4) Cytolysis mechanisms include granzyme secretion by Treg cells and FasL binding to Fas on Teff cells, both inducing Teff‐cell apoptosis.
Figure 2. Foxp3 locus functional domains. Depiction of the different FOXP3 domains and some of the corresponding factors that bind these domains.
Figure 3. T‐cell differentiation and plasticity. Naïve CD4+ T cells differentiate into different effector cell subsets via the upregulation of lineage specifying transcription factors, which is dependent on the cytokine environment they are subjected to. FOXP3+ Treg cells are thought to be plastic as they are capable of upregulating other lineage defining transcription factors such as T‐bet, GATA‐3 and RORγT transiently, by maintaining FOXP3 expression or stably, by downregulating FOXP3 expression. Treg cells can therefore lose their suppressive function and become proinflammatory.
Figure 4. Therapeutic strategies for Treg expansion and functional potentiation in nonhomeostatic conditions. There are two main strategies currently studied for clinical application: in vivo enhancement of Treg‐cell activity and transfer of ex vivo expanded Treg cells. (1) Enhancing endogenous activity by increasing Treg‐cell numbers and potentiating their function have been explored by administering rapamycin, epigenetic modifiers or low doses of IL‐2. (2) Exogenous mechanisms of Treg‐cell expansion include polyclonal expansion or antigen‐specific expansion of Treg cells ex vivo or (3) ex vivo APC (antigen‐presenting cells) therapy on DCs.
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References

Bacchetta R, Bigler M, Touraine JL, et al. (1994) High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. Journal of Experimental Medicine 179: 493–502.

Barbi J, Pardoll D and Pan F (2014) Treg functional stability and its responsiveness to the microenvironment. Immunological Reviews 259: 115–139.

Battaglia M, Stabilini A and Roncarolo MG (2005) Rapamycin selectively expands CD4 + CD25 + FoxP3+ regulatory T cells. Blood 105: 4743–4748.

Bin Dhuban K, Kornete M, S Mason E and Piccirillo CA (2014) Functional dynamics of Foxp3(+) regulatory T cells in mice and humans. Immunological Reviews 259: 140–158.

Bin Dhuban K, d'Hennezel E, Nashi E, et al. (2015) Coexpression of TIGIT and FCRL3 identifies Helios + human memory regulatory T cells. Journal of Immunology (Baltimore, Md.: 1950) 194: 3687–3696.

Borsellino G, Kleinewietfeld M, Di Mitri D, et al. (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110: 1225–1232.

Brunkow ME, Jeffery EW, Hjerrild KA, et al. (2001) Disruption of a new forkhead/winged‐helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genetics 27: 68–73.

Brusko TM, Putnam AL and Bluestone JA (2008) Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunological Reviews 223: 371–390.

Chen Y, Kuchroo VK, Inobe J, Hafler DA and Weiner HL (1994) Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science (New York, N.Y.) 265: 1237–1240.

Choi SW, Braun T, Chang L, et al. (2014) Vorinostat plus tacrolimus and mycophenolate to prevent graft‐versus‐host disease after related‐donor reduced‐intensity conditioning allogeneic haemopoietic stem‐cell transplantation: a phase 1/2 trial. The Lancet Oncology 15: 87–95.

Collison LW, Workman CJ, Kuo TT, et al. (2007) The inhibitory cytokine IL‐35 contributes to regulatory T‐cell function. Nature 450: 566–569.

Colombo MP and Piconese S (2007) Regulatory‐T‐cell inhibition versus depletion: the right choice in cancer immunotherapy. Nature Reviews. Cancer 7: 880–887.

Duan Y, Jia Y, Wang T, et al. (2015) Potent therapeutic target of inflammation, virus and tumor: focus on interleukin‐27. International Immunopharmacology 26: 139–146.

Gagliani N, Magnani CF, Huber S, et al. (2013) Coexpression of CD49b and LAG‐3 identifies human and mouse T regulatory type 1 cells. Nature Medicine 19: 739–746.

Gondek DC, Lu LF, Quezada SA, Sakaguchi S and Noelle RJ (2005) Cutting edge: contact‐mediated suppression by CD4 + CD25+ regulatory cells involves a granzyme B‐dependent, perforin‐independent mechanism. Journal of Immunology (Baltimore, Md.: 1950) 174: 1783–1786.

d'Hennezel E, Kornete M and Piccirillo CA (2010) IL‐2 as a therapeutic target for the restoration of Foxp3+ regulatory T cell function in organ‐specific autoimmunity: implications in pathophysiology and translation to human disease. Journal of Translational Medicine 8: 113.

Hori S, Nomura T and Sakaguchi S (2017) Pillars article: Control of regulatory T cell development by the transcription factor Foxp3. Science 2003. 299: 1057–1061. Journal of Immunology (Baltimore, Md.: 1950) 198: 981–985.

Hu H, Djuretic I, Sundrud MS and Rao A (2007) Transcriptional partners in regulatory T cells: Foxp3, Runx and NFAT. Trends in Immunology 28: 329–332.

Janssens W, Carlier V, Wu B, et al. (2003) CD4 + CD25+ T cells lyse antigen‐presenting B cells by Fas‐Fas ligand interaction in an epitope‐specific manner. Journal of Immunology (Baltimore, Md.: 1950) 171: 4604–4612.

Kim BS, Kim JY, Kim EJ, et al. (2016) Role of thalidomide on the expression of OX40, 4‐1BB, and GITR in T cell subsets. Transplantation Proceedings 48: 1270–1274.

Klein M and Bopp T (2016) Cyclic AMP represents a crucial component of Treg cell‐mediated immune regulation. Frontiers in Immunology 7: 315.

Koreth J, Matsuoka K, Kim HT, et al. (2011) Interleukin‐2 and regulatory T cells in graft‐versus‐host disease. The New England Journal of Medicine 365: 2055–2066.

Lanoue A, Bona C, von Boehmer H and Sarukhan A (1997) Conditions that induce tolerance in mature CD4+ T cells. Journal of Experimental Medicine 185: 405–414.

Li B, Samanta A, Song X, et al. (2007) FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proceedings of the National Academy of Sciences of the United States of America 104: 4571–4576.

Li MO and Rudensky AY (2016) T cell receptor signalling in the control of regulatory T cell differentiation and function. Nature Reviews. Immunology 16: 220–233.

Long SA, Rieck M, Sanda S, et al. (2012) Rapamycin/IL‐2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta‐cell function. Diabetes 61: 2340–2348.

Lopes JE, Torgerson TR, Schubert LA, et al. (2006) Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. Journal of Immunology (Baltimore, Md.: 1950) 177: 3133–3142.

Mantel PY, Kuipers H, Boyman O, et al. (2007) GATA3‐driven Th2 responses inhibit TGF‐beta1‐induced FOXP3 expression and the formation of regulatory T cells. PLoS Biology 5: e329.

Mondino A and Mueller DL (2007) mTOR at the crossroads of T cell proliferation and tolerance. Seminars in Immunology 19: 162–172.

Moreau A, Alliot‐Licht B, Cuturi MC and Blancho G (2016) Tolerogenic dendritic cell therapy in organ transplantation. Transplant International: Official Journal of the European Society for Organ Transplantation 30 (8): 754–764.

Mueller DL (2010) Mechanisms maintaining peripheral tolerance. Nature Immunology 11: 21–27.

Murakami N and Riella LV (2014) Co‐inhibitory pathways and their importance in immune regulation. Transplantation 98: 3–14.

Murray HW, Lu CM, Mauze S, et al. (2002) Interleukin‐10 (IL‐10) in experimental visceral leishmaniasis and IL‐10 receptor blockade as immunotherapy. Infection and Immunity 70: 6284–6293.

Nishizuka Y and Sakakura T (1969) Thymus and reproduction: sex‐linked dysgenesia of the gonad after neonatal thymectomy in mice. Science (New York, N.Y.) 166: 753–755.

Oberle N, Eberhardt N, Falk CS, Krammer PH and Suri‐Payer E (2007) Rapid suppression of cytokine transcription in human CD4 + CD25 T cells by CD4 + Foxp3+ regulatory T cells: independence of IL‐2 consumption, TGF‐beta, and various inhibitors of TCR signaling. Journal of Immunology (Baltimore, Md.: 1950) 179: 3578–3587.

Petrillo MG, Ronchetti S, Ricci E, et al. (2015) GITR+ regulatory T cells in the treatment of autoimmune diseases. Autoimmunity Reviews 14: 117–126.

Richards DM, Delacher M, Goldfarb Y, et al. (2015) Treg cell differentiation: from thymus to peripheral tissue. Progress in Molecular Biology and Translational Science 136: 175–205.

Rifa'i M, Kawamoto Y, Nakashima I and Suzuki H (2004) Essential roles of CD8 + CD122+ regulatory T cells in the maintenance of T cell homeostasis. Journal of Experimental Medicine 200: 1123–1134.

Routes JM and Verbsky JW (2017) Immunodeficiency presenting as an undiagnosed disease. Pediatric Clinics of North America 64: 27–37.

Rubtsov YP, Rasmussen JP, Chi EY, et al. (2008) Regulatory T cell‐derived interleukin‐10 limits inflammation at environmental interfaces. Immunity 28: 546–558.

Sage PT and Sharpe AH (2016) T follicular regulatory cells. Immunological Reviews 271: 246–259.

Seddiki N, Santner‐Nanan B, Martinson J, et al. (2006) Expression of interleukin (IL)‐2 and IL‐7 receptors discriminates between human regulatory and activated T cells. Journal of Experimental Medicine 203: 1693–1700.

Valk E, Rudd CE and Schneider H (2008) CTLA‐4 trafficking and surface expression. Trends in Immunology 29: 272–279.

Weiner HL (2001) Induction and mechanism of action of transforming growth factor‐beta‐secreting Th3 regulatory cells. Immunological Reviews 182: 207–214.

Williams LM and Rudensky AY (2007) Maintenance of the Foxp3‐dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nature Immunology 8: 277–284.

Workman CJ and Vignali DA (2005) Negative regulation of T cell homeostasis by lymphocyte activation gene‐3 (CD223). Journal of Immunology (Baltimore, Md.: 1950) 174: 688–695.

Wortel CM and Heidt S (2017) Regulatory B cells: phenotype, function and role in transplantation. Transplant Immunology 41: 1–9.

Yurchenko E, Shio MT, Huang TC, et al. (2012) Inflammation‐driven reprogramming of CD4+ Foxp3+ regulatory T cells into pathogenic Th1/Th17 T effectors is abrogated by mTOR inhibition in vivo. PLoS One 7: e35572.

Zheng Y, Josefowicz S, Chaudhry A, et al. (2010) Role of conserved non‐coding DNA elements in the Foxp3 gene in regulatory T‐cell fate. Nature 463: 808–812.

Zhou X, Bailey‐Bucktrout SL, Jeker LT, et al. (2009) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nature Immunology 10: 1000–1007.

Further Reading

Benoist C and Mathis D (2012) Treg cells, life history, and diversity. Cold Spring Harbor Perspectives in Biology 4: a007021.

Daley SR, Teh C, Hu DY, Strasser A and Gray DHD (2017) Cell death and thymic tolerance. Immunological Reviews 277: 9–20.

d'Hennezel E, Ben‐Shoshan M, Ochs HD, et al. (2009) FOXP3 forkhead domain mutation and regulatory T cells in the IPEX syndrome. New England Journal of Medicine 361: 1710–1713.

Rudensky AY (2011) Regulatory T cells and Foxp3. Immunological Reviews 241: 260–268.

Yadav M, Stephan S and Bluestone JA (2013) Peripherally induced tregs ‐ role in immune homeostasis and autoimmunity. Frontiers in Immunology 4: 232.

Zhou L, Chong MM and Littman DR (2009) Plasticity of CD4+ T cell lineage differentiation. Immunity 30: 646–655.

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Bartolucci, Sabrina, and Piccirillo, Ciriaco A(Dec 2017) Immune Regulation in Human Health and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000952.pub2]