Immune Regulation in Human Health and Disease


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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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.

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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. [doi: 10.1002/9780470015902.a0000952.pub2]