T helper 3 cell (Th3)
editT helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosupressive functions, that can be induced by administration of foreign oral antigen.[1] Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). They have been described both in mice and human as CD4+FoxP3- regulatory T cells.[2] Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25-FoxP3-LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.[3]
Th3 phenotype and secreted molecules
edit
Th3 cells are characterised as CD4+CD25-CD69+FoxP3-LAP+ cells. Unlike the well characterised T regulatory (Treg) cells, Th3 cells do not express transcription factor FoxP3. There is a lack of specific transcription factor for full and reliable recognition of the Th3 cell population.[2]
Type II-lectin receptor CD69 is presented on cell surface shortly after activation. The presence of CD69 is not specific for Th3 cells, since it is expressed on other lymphocytes, mainly subsets that are tissue resident.[4] The latency-associated peptide (LAP) noncovalently bounds mature TGF-β and can be expressed by many cells of the immune system.[5]
In tumors Th3 cells can express lymphocyte activation gene-3 (LAG3). Th3 cells produce vast amounts of TGF-β and to a lesser degree also the anti-inflammatory cytokine interleukin-10 (IL-10). In colorectal cancer they were described as 50 times more potent immune suppressor than the classical regulatory FoxP3+ T lymphocytes and their functions was mainly mediated by secretion of suppresive cytokines.[6]
LAG3 acts as a negative regulator of T cell activation and function and can also be expressed on NK cells and other T cells, than Th3. Because of its structural similarity to CD4, LAG3 can bind MHC class II molecules.[7]
Activation and effector functions
editTh3 cells can be activated by TCR stimulation after the recognition of an antigen or induced from CD4+ T lymphocytes by TGF-β in the presence of IL-10 and IL-4 cytokines.[8]
Th3 participate in the regulation of the immune response via mechanisms independent on cell-to-cell contact. Secretion of anti-inflammatory cytokine TGF-β by Th3 cells helps to maintain homeostasis in the gut and suppress exaggerated inflammatory and autoimmune responses in the body. TGF-β is a crucial cytokine for maintaining the naturally ocurring Treg cells, that suppress Th1 and Th2 immune functions. [3] Th3 cells can also directly suppress Th1 and Th2 cells by secretion of TGF-β and provide help for IgA secretion.[1]
- ^ a b Gol-Ara, Maryam; Jadidi-Niaragh, Farhad; Sadria, Reza; Azizi, Gholamreza; Mirshafiey, Abbas (2012-10-24). "The Role of Different Subsets of Regulatory T Cells in Immunopathogenesis of Rheumatoid Arthritis". Arthritis. Retrieved 2020-05-30.
- ^ a b Chien, Chien-Hui; Chiang, Bor-Luen (2017-11-18). "Regulatory T cells induced by B cells: a novel subpopulation of regulatory T cells". Journal of Biomedical Science. 24. doi:10.1186/s12929-017-0391-3. ISSN 1021-7770. PMC 5694621. PMID 29151021.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b Weiner, Howard L.; da Cunha, Andre Pires; Quintana, Francisco; Wu, Henry (2011-5). "Oral tolerance". Immunological Reviews. 241 (1): 241–259. doi:10.1111/j.1600-065X.2011.01017.x. ISSN 0105-2896. PMC 3296283. PMID 21488901.
{{cite journal}}: Check date values in:|date=(help) - ^ Cibrián, Danay; Sánchez-Madrid, Francisco (2017-6). "CD69: from activation marker to metabolic gatekeeper". European journal of immunology. 47 (6): 946–953. doi:10.1002/eji.201646837. ISSN 0014-2980. PMC 6485631. PMID 28475283.
{{cite journal}}: Check date values in:|date=(help) - ^ Boswell, Sandra; Sharif, Shayan; Alisa, Akeel; Pereira, Stephen P; Williams, Roger; Behboudi, Shahriar (2011-7). "Induction of latency-associated peptide (transforming growth factor-β1) expression on CD4+ T cells reduces Toll-like receptor 4 ligand-induced tumour necrosis factor-α production in a transforming growth factor-β-dependent manner". Immunology. 133 (3): 278–287. doi:10.1111/j.1365-2567.2011.03425.x. ISSN 0019-2805. PMC 3112337. PMID 21426338.
{{cite journal}}: Check date values in:|date=(help) - ^ Scurr, M; Ladell, K; Besneux, M; Christian, A; Hockey, T; Smart, K; Bridgeman, H; Hargest, R; Phillips, S; Davies, M; Price, D (2014-03). "Highly prevalent colorectal cancer-infiltrating LAP+ Foxp3− T cells exhibit more potent immunosuppressive activity than Foxp3+ regulatory T cells". Mucosal Immunology. 7 (2): 428–439. doi:10.1038/mi.2013.62. ISSN 1933-0219. PMC 3931584. PMID 24064667.
{{cite journal}}: Check date values in:|date=(help) - ^ Andrews, Lawrence P.; Marciscano, Ariel E.; Drake, Charles G.; Vignali, Dario A.A. (2017-3). "LAG3 (CD223) as a Cancer Immunotherapy Target". Immunological reviews. 276 (1): 80–96. doi:10.1111/imr.12519. ISSN 0105-2896. PMC 5338468. PMID 28258692.
{{cite journal}}: Check date values in:|date=(help) - ^ Jørgensen, Nanna; Persson, Gry; Hviid, Thomas Vauvert F. (2019). "The Tolerogenic Function of Regulatory T Cells in Pregnancy and Cancer". Frontiers in Immunology. 10. doi:10.3389/fimmu.2019.00911. ISSN 1664-3224.
{{cite journal}}: CS1 maint: unflagged free DOI (link)