Regulatory T cells (Tregs) and their therapeutic potential against autoimmune disorders – Advances and challenges

Figures & data

Figure 1. Classification, phenotypes, functional characteristics, and balance of Treg cells in the immune response. (a) Differentiation of naive CD4 + T cells into Tregs or effector T cells. The selection of naïve CD4 + T cells and natural Tregs occurs in the thymus. Naïve CD4 + T cells, subsequently, can differentiate into various different T cell subsets: Th1, Th2, Th17, induced Tregs (iTregs), in the periphery, all heralding distinct immunological functions. These differentiation programs are regulated by different cytokines. The transcription factors T-bet and Runx3, GATA3, or RORγt, are required to differentiate naive T cells into Th1, Th2, or Th17 cells, respectively. For example: T-bet (Th1 cells), GATA3 (Th2 cells), RORγt (Th17 cells), FOXP3 (Tregs). (b) In a healthy individual, the immune system is under regular homeostasis, can suppress autoreactive effector T cells and control a fine balance (left). Aberrant Treg plasticity, quantitative and functional deficiencies of Treg impair immune homeostasis and result in autoimmune diseases (right). Abbreviations: nTreg: natural Treg; iTreg: induced Treg; FOXP3: forkhead Box P3; RA: retinoic acid; CD: cluster of differentiation; IFN: interferon; IL: interleukin; RORγt: retinoid related orphan receptor γ; T-bet: T box transcription factor; TCR: T cell receptor; TGF-β: transforming growth factor-β; Th: T helper cell; GATA3: GATA-binding factor 3; Tfh: follicular helper T cells; Bcl: B-cell lymphoma 2. Figure was designed by Biorender.com program (https://biorender.com/). Accessed on 13 April 2021.

Figure 2. Mechanisms underlying Treg-mediated immunosuppression. Treg cells regulate immune responses by suppressing the functions of effector T cells (Teff) and antigen-presenting cells (APCs) through various mechanisms, including (i) modulation of dendritic cell (DC) function and prevention of DC maturation by the interaction of CTLA4 and LAG3 expressed by Treg cells and the CD80/86 costimulatory molecules and MHC class II expressed by DC, respectively, leading to IDO generation and inhibition of Teff cell activation; (ii) metabolic disruption, Treg cells can disrupt metabolic roles by the expression of the ectoenzymes CD39/73 allowing adenosine generation and binding of adenosine to the adenosine receptor 2A (A2AR) exposed on Teff cells, or by IL-2 deprivation; (iii) generation and secretion of the anti-inflammatory cytokines IL-10, IL-35, and TGF-β that restrain Th1 and Th17 immune responses and the production of IFN-γ and IL-17, respectively; and (iv) direct cytotoxicity, Treg cells can also induce direct killing of effector cells by the release of granzyme A, granzyme B, and perforin, which induce apoptosis in the target cells. Tregs have also been detected to have a direct effect on B-cells via PD-L1/PD-1 interaction. Abbreviations: APC: antigen presenting cell; TGF-β: transforming growth factor-β; A2AR: Adenosine receptor 2A; IL: interleukin; IFN: interferon; Teff: effector T cells; Treg: regulatory T cells; CD: cluster differentiation; IDO: indoleamine 2,3-dioxygenase; DC: dendritic cell; CTLA-4: cytotoxic T lymphocyte antigen-4; TGF-β: transforming growth factor-β; LAG3: lymphocyte-activation gene 3; MHC: major histocompatibility complex; PD-1: programmed death-1; PD-Ls: programmed cell death ligands. Figure was designed by Biorender.com program (https://biorender.com/) Accessed on 13 April 2021.

Table 1. Clinical trials of Tregs against autoimmune diseases

Disease	Expansion: autologous or polyclonal Treg cells	Description of application and dose	Outcome of clinical trial and final status	References
Crohn`s disease	PBMC derived ovalbumin specific Treg cells expanded under in vitro condition designated as ovasve NCT02327221	Single infusionof cells ranging from 10^6 to 10^9in number per patients	Well tolerated yet adverse effect has been observed in 54 patients, all recovered without showing any further adverse effect	64
Croh`n disease	Polyclonally expanded autologous CD4+ CD25+ CD127lowCD45RA+Tregs treated with rapamycin and retinoic acid receptor agonistNCT03185000	0.5–1 x 10 ^6 cells up to 8–0 × 10 ^6 cells /kg body weight	Expressed α4β7 and exhibit suppressive function with migratory activities in cell culture system. Final results not posted till Nov. 2021	65
Type1 diabetes T1D	Autologous ex vivo Tregs CD4+ CD25+ CD127, lowISRCTN06128462	10 x 10^6–30 × 0^6per kg body weight	Absence of serious adverse effect without insulin dependency. Clinical trials completed	58
T1D	Autologous enriched Tregs derived from PBMC, ex vivo expandedNCT01210664	0.5 x 10 ^8 to 26 × 10 ^8 Tregs infused as single dose via i/v route per patient	About 25% of peak level of circulatory Tregs persisted for one year after transfer. Transient increase in FOXP3(+)CD4(+)CD25(hi)CD127(lo) phenotype Tregs in recipients was observed. Adverse effect was observed in 3 out of 14 patients, not related to cell infusion. Ddeuterium labeling was absent in non-Treg cells indicating Tregs stability. C-peptide indicator of insulin production persisted up to 2 years of Treg cell transfer. Clinical trials completed	66
T1D	CD4 + CD25 + CD127 lowTregs derived from autologous PBMCenriched under in-vitro condition, under Phase-I. Clinical trial NCT02772679	3 x 10 ^6–20 × 10 ^6 cells per kg, s/c route	No result posted as on November 2021	35
T1D	Umbilical cord blood derived TregsPhase-I and Phase-II trialNCT02932826	Tregs with insulin and insulin alone	40 participants were incorporated in the trial and result not published till Nov 2021	35
Active cutaneous lupus	Autologous ex vivo expanded and enriched Tregs, under Phase-I. Clinical trials NCT02428309	1 x 10 ^8 deuterium labeled Tregs cells per patients	Increase population of Tregs and IL-17 production by both CD4 and CD8 cells recorded in skin biopsies. Terminated due to participantrecruitment feasibility	67
Pemphigus Vulgaris	Ex vivo expanded autologous CD4+ CD127lo/negCD25polyclonal TregsNCT03239470	1.0 x 10 ^8 and2.5 x 10 ^8 cells per patients of 18 to 75 years age	Recovery criteria was to detect CD4+, CD25++, CD127 low Treg in patients using cell shorting system. Results submitted during October 2021 but detail is under quality control process for further recruiting,	68
Auto immune hepatitis	Polyclonally expanded autologous Tregs for phase I/II clinical trials NCT02704338	10–20 × 10 ^6 cells in a single infusion to patients aged between 10–70 years	Initiated at Nanjing Medical University China. Further information not yet published	35

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