Research progress on the role of regulatory T cells in ocular surface diseases

doi:10.3969/j.issn.1674-8115.2022.08.021

Abstract

Abstract:

As the external barrier of the eyeball, the ocular surface tissue, composed of the cornea, the conjunctiva, the eyelids, the meibomian glands, and the lacrimal gland, is exposed to the environment. In addition to keeping the cornea smooth and wet, the ocular surface is equipped with immune cells and related factors, which are capable of fighting against pathogens through innate and adaptive immune responses and preventing unnecessary or excessive inflammatory reactions against autoantigens or harmless foreign antigens through several regulatory mechanisms. The disorder of immune regulation is at the core of many ocular surface diseases. As an important part of the ocular surface microenvironment, regulatory T cells (Treg cells) actively participate in the suppression of abnormal or excessive immune responses towards the auto, microbial and environmental antigens through various mechanisms, and play a key role in inducing immune tolerance and regulating immune balance. Functional and numerical defects of Treg cells can trigger disruption of the immune homeostasis, leading to or promoting the occurrence of ocular surface diseases. In recent years, more and more researchers are focusing on the role and related molecular mechanisms of Treg cells in the occurrence and development of ocular surface diseases. Some preclinical studies have shown that Treg cell-related immunotherapy has great therapeutic potential in ocular surface diseases. Therefore, this article reviews the biological functions of Treg cells and their roles in the ocular surface diseases, such as dry eye disease, allergic diseases, infectious diseases, corneal transplantation rejection, and tissue repair, and then discusses the promising application prospects of Treg cells therapy in the field.

Key words: regulatory T cell, ocular surface disease, immune regulation, inflammation, cell therapy

CLC Number:

A Tingxi, SHAO Chunyi, FU Yao. Research progress on the role of regulatory T cells in ocular surface diseases[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(8): 1145-1150.

TrendMD

References 64

1	GERSHON R K, KONDO K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes[J]. Immunology, 1970, 18(5): 723-737.
2	SAKAGUCHI S, SAKAGUCHI N, ASANO M, 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]. J Immunol, 1995, 155(3): 1151-1164.
3	GALLETTI J G, GUZMÁN M, GIORDANO M N. Mucosal immune tolerance at the ocular surface in health and disease[J]. Immunology, 2017, 150(4): 397-407.
4	GALLETTI J G, DE PAIVA C S. The ocular surface immune system through the eyes of aging[J]. Ocul Surf, 2021, 20: 139-162.
5	HORI J, YAMAGUCHI T, KEINO H, et al. Immune privilege in corneal transplantation[J]. Prog Retin Eye Res, 2019, 72: 100758.
6	GROVER P, GOEL P N, GREENE M I. Regulatory T cells: regulation of identity and function[J]. Front Immunol, 2021, 12: 750542.
7	FONTENOT J D, GAVIN M A, RUDENSKY A Y. Foxp3 programs the development and function of CD4⁺CD25⁺ regulatory T cells[J]. Nat Immunol, 2003, 4(4): 330-336.
8	KOMATSU N, OKAMOTO K, SAWA S, et al. Pathogenic conversion of Foxp3⁺ T cells into TH17 cells in autoimmune arthritis[J]. Nat Med, 2014, 20(1): 62-68.
9	LIU W H, PUTNAM A L, ZHOU X Y, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4⁺ T reg cells[J]. J Exp Med, 2006, 203(7): 1701-1711.
10	SHEVACH E M, THORNTON A M. tTregs, pTregs, and iTregs: similarities and differences[J]. Immunol Rev, 2014, 259(1): 88-102.
11	RAFFIN C, VO L T, BLUESTONE J A. T_reg cell-based therapies: challenges and perspectives[J]. Nat Rev Immunol, 2020, 20(3): 158-172.
12	SANJABI S, OH S A, LI M O. Regulation of the immune response by TGF-β: from conception to autoimmunity and infection[J]. Cold Spring Harb Perspect Biol, 2017, 9(6): a022236.
13	WANG R X, YU C R, DAMBUZA I M, et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease[J]. Nat Med, 2014, 20(6): 633-641.
14	CHINEN T, KANNAN A K, LEVINE A G, et al. An essential role for the IL-2 receptor in T reg cell function[J]. Nat Immunol, 2016, 17(11): 1322-1333.
15	WING J B, ISE W, KUROSAKI T, et al. Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4[J]. Immunity, 2014, 41(6): 1013-1025.
16	YAN Y P, ZHANG G X, GRAN B, et al. IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis[J]. J Immunol, 2010, 185(10): 5953-5961.
17	BAUCHÉ D, JOYCE-SHAIKH B, JAIN R, et al. LAG3⁺ regulatory T cells restrain interleukin-23-producing CX3CR1⁺ gut-resident macrophages during group 3 innate lymphoid cell-driven colitis[J]. Immunity, 2018, 49(2): 342-352.e5.
18	ALMAHARIQ M, MEI F C, WANG H, et al. Exchange protein directly activated by cAMP modulates regulatory T-cell-mediated immunosuppression[J]. Biochem J, 2015, 465(2): 295-303.
19	CAO X F, CAI S F, FEHNIGER T A, et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance[J]. Immunity, 2007, 27(4): 635-646.
20	MUÑOZ-ROJAS A R, MATHIS D. Tissue regulatory T cells: regulatory chameleons[J]. Nat Rev Immunol, 2021, 21(9): 597-611.
21	CRAIG J P, NICHOLS K K, AKPEK E K, et al. TFOS DEWS Ⅱ definition and classification report[J]. Ocular Surf, 2017, 15(3): 276-283.
22	BRON A J, DE PAIVA C S, CHAUHAN S K, et al. TFOS DEWS Ⅱ pathophysiology report[J]. Ocular Surf, 2017, 15(3): 438-510.
23	SCHAUMBURG C S, SIEMASKO K F, DE PAIVA C S, et al. Ocular surface APCs are necessary for autoreactive T cell-mediated experimental autoimmune lacrimal keratoconjunctivitis[J]. J Immunol, 2011, 187(7): 3653-3662.
24	CHEN Y H, CHAUHAN S K, LEE H S, et al. Effect of desiccating environmental stress versus systemic muscarinic AChR blockade on dry eye immunopathogenesis[J]. Invest Ophthalmol Vis Sci, 2013, 54(4): 2457-2464.
25	CHAUHAN S K, EL ANNAN J, ECOIFFIER T, et al. Autoimmunity in dry eye is due to resistance of Th17 to Treg suppression[J]. J Immunol, 2009, 182(3): 1247-1252.
26	SIEMASKO K F, GAO J P, CALDER V L, et al. In vitro expanded CD4⁺CD25⁺Foxp3⁺ regulatory T cells maintain a normal phenotype and suppress immune-mediated ocular surface inflammation[J]. Invest Ophthalmol Vis Sci, 2008, 49(12): 5434-5440.
27	RATAY M L, GLOWACKI A J, BALMERT S C, et al. Treg-recruiting microspheres prevent inflammation in a murine model of dry eye disease[J]. J Control Release, 2017, 258: 208-217.
28	SINGH R B, BLANCO T, MITTAL S K, et al. Pigment epithelium-derived factor enhances the suppressive phenotype of regulatory T cells in a murine model of dry eye disease[J]. Am J Pathol, 2021, 191(4): 720-729.
29	YAO G H, QI J J, LIANG J, et al. Mesenchymal stem cell transplantation alleviates experimental Sjögren's syndrome through IFN-β/IL-27 signaling axis[J]. Theranostics, 2019, 9(26): 8253-8265.
30	XU J J, WANG D D, LIU D Y, et al. Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjögren syndrome[J]. Blood, 2012, 120(15): 3142-3151.
31	NIETO J E, CASANOVA I, SERNA-OJEDA J C, et al. Increased expression of TLR4 in circulating CD4⁺ T cells in patients with allergic conjunctivitis and in vitro attenuation of Th2 inflammatory response by α-MSH[J]. Int J Mol Sci, 2020, 21(21): 7861.
32	GALICIA-CARREÓN J, SANTACRUZ C, AYALA-BALBOA J, et al. An imbalance between frequency of CD4⁺CD25⁺FOXP3⁺ regulatory T cells and CCR4⁺ and CCR9⁺ circulating helper T cells is associated with active perennial allergic conjunctivitis[J]. Clin Dev Immunol, 2013, 2013: 919742.
33	SUMI T, FUKUSHIMA A, FUKUDA K, et al. Thymus-derived CD4⁺ CD25⁺ T cells suppress the development of murine allergic conjunctivitis[J]. Int Arch Allergy Immunol, 2007, 143(4): 276-281.
34	FUKUSHIMA A, SUMI T, ISHIDA W, et al. Depletion of thymus-derived CD4⁺CD25⁺ T cells abrogates the suppressive effects of alpha-galactosylceramide treatment on experimental allergic conjunctivitis[J]. Allergol Int, 2008, 57(3): 241-246.
35	YU W C, GENG S, SUO Y Z, et al. Critical role of regulatory T cells in the latency and stress-induced reactivation of HSV-1[J]. Cell Rep, 2018, 25(9): 2379-2389.e3.
36	LOBO A M, AGELIDIS A M, SHUKLA D. Pathogenesis of herpes simplex keratitis: the host cell response and ocular surface sequelae to infection and inflammation[J]. Ocul Surf, 2019, 17(1): 40-49.
37	SEHRAWAT S, SUVAS S, SARANGI P P, et al. In vitro-generated antigen-specific CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells control the severity of herpes simplex virus-induced ocular immunoinflammatory lesions[J]. J Virol, 2008, 82(14): 6838-6851.
38	SUVAS S, AZKUR A K, KIM B S, et al. CD4⁺ CD25⁺ regulatory T cells control the severity of viral immunoinflammatory lesions[J]. J Immunol, 2004, 172(7): 4123-4132.
39	BHELA S, VARANASI S K, JAGGI U, et al. The plasticity and stability of regulatory T cells during viral-induced inflammatory lesions[J]. J Immunol, 2017, 199(4): 1342-1352.
40	VARANASI S K, REDDY P B J, BHELA S, et al. Azacytidine treatment inhibits the progression of herpes stromal keratitis by enhancing regulatory T cell function[J]. J Virol, 2017, 91(7): e02367-e02316.
41	LAM A J, HOEPPLI R E, LEVINGS M K. Harnessing advances in T regulatory cell biology for cellular therapy in transplantation[J]. Transplantation, 2017, 101(10): 2277-2287.
42	CHAUHAN S K, SABAN D R, LEE H K, et al. Levels of Foxp3 in regulatory T cells reflect their functional status in transplantation[J]. J Immunol, 2009, 182(1): 148-153.
43	HORI J, TANIGUCHI H, WANG M C, et al. GITR ligand-mediated local expansion of regulatory T cells and immune privilege of corneal allografts[J]. Invest Ophthalmol Vis Sci, 2010, 51(12): 6556-6565.
44	INOMATA T, HUA J, DI ZAZZO A, et al. Impaired function of peripherally induced regulatory T cells in hosts at high risk of graft rejection[J]. Sci Rep, 2016, 6: 39924.
45	INOMATA T, HUA J, NAKAO T, et al. Corneal tissue from dry eye donors leads to enhanced graft rejection[J]. Cornea, 2018, 37(1): 95-101.
46	HUA J, INOMATA T, CHEN Y H, et al. Pathological conversion of regulatory T cells is associated with loss of allotolerance[J]. Sci Rep, 2018, 8(1): 7059.
47	TAHVILDARI M, OMOTO M, CHEN Y H, et al. In vivo expansion of regulatory T cells by low-dose interleukin-2 treatment increases allograft survival in corneal transplantation[J]. Transplantation, 2016, 100(3): 525-532.
48	SHAO C Y, CHEN Y H, NAKAO T, et al. Local delivery of regulatory T cells promotes corneal allograft survival[J]. Transplantation, 2019, 103(1): 182-190.
49	LI J T, TAN J, MARTINO M M, et al. Regulatory T-cells: potential regulator of tissue repair and regeneration[J]. Front Immunol, 2018, 9: 585.
50	SCHIAFFINO S, PEREIRA M G, CICILIOT S, et al. Regulatory T cells and skeletal muscle regeneration[J]. FEBS J, 2017, 284(4): 517-524.
51	NOSBAUM A, PREVEL N, TRUONG H A, et al. Cutting edge: regulatory T cells facilitate cutaneous wound healing[J]. J Immunol, 2016, 196(5): 2010-2014.
52	ALI N W, ZIRAK B, RODRIGUEZ R S, et al. Regulatory T cells in skin facilitate epithelial stem cell differentiation[J]. Cell, 2017, 169(6): 1119-1129.e11.
53	LI J T, YANG K Y, TAM R C Y, et al. Regulatory T-cells regulate neonatal heart regeneration by potentiating cardiomyocyte proliferation in a paracrine manner[J]. Theranostics, 2019, 9(15): 4324-4341.
54	YAN D, YU F, CHEN L B, et al. Subconjunctival injection of regulatory T cells potentiates corneal healing via orchestrating inflammation and tissue repair after acute alkali burn[J]. Invest Ophthalmol Vis Sci, 2020, 61(14): 22.
55	ARPAIA N, GREEN J A, MOLTEDO B, et al. A distinct function of regulatory T cells in tissue protection[J]. Cell, 2015, 162(5): 1078-1089.
56	COCO G, FOULSHAM W, NAKAO T, et al. Regulatory T cells promote corneal endothelial cell survival following transplantation via interleukin-10[J]. Am J Transplant, 2020, 20(2): 389-398.
57	ALTSHULER A, AMITAI-LANGE A, TARAZI N, et al. Discrete limbal epithelial stem cell populations mediate corneal homeostasis and wound healing[J]. Cell Stem Cell, 2021, 28(7): 1248-1261.e8.
58	PILAT N, SPRENT J. Treg therapies revisited: tolerance beyond deletion[J]. Front Immunol, 2021, 11: 622810.
59	MACDONALD K N, PIRET J M, LEVINGS M K. Methods to manufacture regulatory T cells for cell therapy[J]. Clin Exp Immunol, 2019, 197(1): 52-63.
60	BRUNSTEIN C G, MILLER J S, MCKENNA D H, et al. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect[J]. Blood, 2016, 127(8): 1044-1051.
61	BLUESTONE J A, BUCKNER J H, FITCH M, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells[J]. Sci Transl Med, 2015, 7(315): 315ra189.
62	DESREUMAUX P, FOUSSAT A, ALLEZ M, et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease[J]. Gastroenterology, 2012, 143(5): 1207-1217.e2.
63	SAADOUN D, ROSENZWAJG M, JOLY F, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis[J]. N Engl J Med, 2011, 365(22): 2067-2077.
64	KORETH J, MATSUOKA K I, KIM H T, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease[J]. N Engl J Med, 2011, 365(22): 2055-2066.

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