T helper 17 cell

{{Short description|Subset of pro-inflammatory T helper cells}} '''T helper 17 cells''' ('''T_h17''') are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause T_h17s to actually inhibit T_reg differentiation.<ref>{{cite journal | vauthors = Hartigan-O'Connor DJ, Hirao LA, McCune JM, Dandekar S | title = Th17 cells and regulatory T cells in elite control over HIV and SIV | journal = Current Opinion in HIV and AIDS | volume = 6 | issue = 3 | pages = 221–7 | date = May 2011 | pmid = 21399494 | pmc = 4079838 | doi = 10.1097/COH.0b013e32834577b3 }}</ref> However, T_h17s are developmentally distinct from T_h1 and T_h2 lineages. T_h17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic T_h17 cells have been termed as '''T_reg17 cells'''.<ref>{{cite journal | vauthors = Singh B, Schwartz JA, Sandrock C, Bellemore SM, Nikoopour E | title = Modulation of autoimmune diseases by interleukin (IL)-17 producing regulatory T helper (T_h17) cells | journal = The Indian Journal of Medical Research | volume = 138 | issue = 5 | pages = 591–4 | date = November 2013 | pmid = 24434314 | pmc = 3928692 }}</ref>

They have also been implicated in autoimmune and inflammatory disorders. The loss of T_h17 cell populations at mucosal surfaces has been linked to chronic inflammation and microbial translocation. These regulatory T_h17 cells can be generated by TGF-beta plus IL-6 in vitro.

==Differentiation== Like conventional regulatory T cells (T_reg), induction of regulatory T_reg17 cells could play an important role in modulating and preventing certain autoimmune diseases. T_reg17 (Regulatory T_h17) cells are generated from CD4⁺ T&nbsp;cells.

Transforming growth factor beta (TGF-β), interleukin 6 (IL-6), interleukin 21 (IL-21) and interleukin 23 (IL-23) contribute to T_h17 formation in mice and humans. Key factors in the differentiation of T_h17 cells are signal transducer and the activator of transcription 3 (Stat3) and retinoic acid receptor-related orphan receptors gamma (RORγ) and alpha (RORα).<ref name="pmid16990136">{{cite journal | vauthors = Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR | display-authors = 6 | title = The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells | journal = Cell | volume = 126 | issue = 6 | pages = 1121–33 | date = September 2006 | pmid = 16990136 | doi = 10.1016/j.cell.2006.07.035 | s2cid = 9034013 | doi-access = free }}</ref> T_h17 cells are differentiated when naive T cells are exposed to the cytokines mentioned above. These cytokines are produced by activated antigen presenting cells (APCs) after contact with pathogens.<ref>{{cite journal | vauthors = Guglani L, Khader SA | title = Th17 cytokines in mucosal immunity and inflammation | journal = Current Opinion in HIV and AIDS | volume = 5 | issue = 2 | pages = 120–7 | date = March 2010 | pmid = 20543588 | pmc = 2892849 | doi = 10.1097/coh.0b013e328335c2f6 }}</ref> The T_h17 cells can alter their differentiation program ultimately giving rise to either protective or pro-inflammatory pathogenic cells. The protective and non-pathogenic T_h17 cells induced by IL-6 and TGF-β are termed as T_reg17&nbsp;cells. The pathogenic T_h17 cells are induced by IL-23 and IL-1β.<ref>{{cite journal | vauthors = Singh B, Schwartz JA, Sandrock C, Bellemore SM, Nikoopour E | title = Modulation of autoimmune diseases by interleukin (IL)-17 producing regulatory T helper (Th17) cells | journal = The Indian Journal of Medical Research | volume = 138 | issue = 5 | pages = 591–4 | date = November 2013 | pmid = 24434314 | pmc = 3928692 }}</ref> IL-21, produced by T_h17 cells themselves, has also been shown to initiate an alternative route for the activation of T_h17 populations.<ref name="Korn2007">{{cite journal | vauthors = Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, Oukka M, Kuchroo VK | display-authors = 6 | title = IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells | journal = Nature | volume = 448 | issue = 7152 | pages = 484–487 | date = July 2007 | pmid = 17581588 | pmc = 3805028 | doi = 10.1038/nature05970 | bibcode = 2007Natur.448..484K }}</ref> Both interferon gamma (IFNγ) and IL-4, the main stimulators of T_h1 and T_h2 differentiation, respectively, have been shown to inhibit T_h17 differentiation.{{citation needed|reason=reliable source needed|date=June 2015}}

Similar to T_h17 cells the T_reg17 development depended on the transcription factor Stat3.<ref>{{cite journal | vauthors = Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A, Rudensky AY | title = CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner | journal = Science | volume = 326 | issue = 5955 | pages = 986–91 | date = November 2009 | pmid = 19797626 | pmc = 4408196 | doi = 10.1126/science.1172702 | bibcode = 2009Sci...326..986C }}</ref>

== Function == T_h17 cells play a role in adaptive immunity protecting the body against pathogens. However, anti-fungal immunity appears to be limited to particular sites with detrimental effects observed.<ref>{{cite journal | vauthors = Vautier S, Sousa M, Brown GD | title = C-type lectins, fungi and Th17 responses | journal = Cytokine & Growth Factor Reviews | volume = 21 | issue = 6 | pages = 405–12 | date = December 2010 | pmid = 21075040 | pmc = 3001956 | doi = 10.1016/j.cytogfr.2010.10.001 }}</ref> Their main effector cytokines are IL-17A, IL-17F, IL-21, and IL-22,<ref name="pmid23459074">{{cite journal | vauthors = Zambrano-Zaragoza JF, Romo-Martínez EJ, Durán-Avelar M, García-Magallanes N, Vibanco-Pérez N | title = Th17 cells in autoimmune and infectious diseases | journal = International Journal of Inflammation | volume = 2014 | article-number = 651503 | date = Aug 2014 | pmid = 25152827 | pmc = 4137509 | doi = 10.1155/2014/651503 | doi-access = free }}</ref> as well as granulocyte-macrophage colony-stimulating factor (GM-CSF). IL-17 family cytokines (IL-17A and IL-17F) target innate immune cells and epithelial cells, among others, to produce G-CSF and IL-8 (CXCL8), which leads to '''''neutrophil'' production and recruitment'''. In this way, T_h17 cell lineage appears to be one of the three major subsets of effector T cells, as these cells are involved in regulation of neutrophils, while T_h2 cells regulate eosinophils, basophils and mast cells, and T_h1 cells regulate macrophages and monocytes.<ref>{{cite journal | vauthors = Weaver CT, Elson CO, Fouser LA, Kolls JK | title = The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin | journal = Annual Review of Pathology | volume = 8 | issue = 1 | pages = 477–512 | date = January 2013 | pmid = 23157335 | pmc = 3965671 | doi = 10.1146/annurev-pathol-011110-130318 }}</ref> Thus, three T helper cell subsets are able to influence the myeloid part of the immune system, largely responsible for innate defense against pathogens.

T_reg17 cells with regulatory phenotype with ''in vivo'' immune-suppressive properties in the gut have also been identified as rT_h17 cells.<ref>{{cite journal | vauthors = Esplugues E, Huber S, Gagliani N, Hauser AE, Town T, Wan YY, O'Connor W, Rongvaux A, Van Rooijen N, Haberman AM, Iwakura Y, Kuchroo VK, Kolls JK, Bluestone JA, Herold KC, Flavell RA | display-authors = 6 | title = Control of TH17 cells occurs in the small intestine | journal = Nature | volume = 475 | issue = 7357 | pages = 514–8 | date = July 2011 | pmid = 21765430 | pmc = 3148838 | doi = 10.1038/nature10228 }}</ref>

T_reg17 cells produce IL-17 and IL-10 and low level of IL-22 and suppress autoimmune and other immune responses. CD4⁺ T&nbsp;cells polarized with IL-23 and IL-6 are pathogenic upon adoptive transfer in type 1 diabetes while cells polarized with TGF-beta and IL-6 are not pathogenic.,<ref>{{cite journal | vauthors = Bellemore SM, Nikoopour E, Schwartz JA, Krougly O, Lee-Chan E, Singh B | title = Preventative role of interleukin-17 producing regulatory T helper type 17 (Treg 17) cells in type 1 diabetes in non-obese diabetic mice | journal = Clinical and Experimental Immunology | volume = 182 | issue = 3 | pages = 261–9 | date = December 2015 | pmid = 26250153 | pmc = 4636888 | doi = 10.1111/cei.12691 }}</ref><ref>{{cite journal | vauthors = Nikoopour E, Schwartz JA, Huszarik K, Sandrock C, Krougly O, Lee-Chan E, Singh B | title = Th17 polarized cells from nonobese diabetic mice following mycobacterial adjuvant immunotherapy delay type 1 diabetes | journal = Journal of Immunology | volume = 184 | issue = 9 | pages = 4779–88 | date = May 2010 | pmid = 20363968 | doi = 10.4049/jimmunol.0902822 | s2cid = 207422604 | doi-access = }}</ref> The intracellular aryl hydrocarbon receptor (AhR), which is activated by certain aromatic compounds, is specifically expressed in T_reg17 cells.<ref>{{cite journal | vauthors = Stockinger B, Di Meglio P, Gialitakis M, Duarte JH | title = The aryl hydrocarbon receptor: multitasking in the immune system | journal = Annual Review of Immunology | volume = 32 | pages = 403–32 | year = 2014 | pmid = 24655296 | doi = 10.1146/annurev-immunol-032713-120245 | doi-access = free }}</ref> These cells are regulated by IL-23 and TGF-beta.<ref>{{cite journal | vauthors = Kluger MA, Luig M, Wegscheid C, Goerke B, Paust HJ, Brix SR, Yan I, Mittrücker HW, Hagl B, Renner ED, Tiegs G, Wiech T, Stahl RA, Panzer U, Steinmetz OM | display-authors = 6 | title = Stat3 programs Th17-specific regulatory T cells to control GN | journal = Journal of the American Society of Nephrology | volume = 25 | issue = 6 | pages = 1291–302 | date = June 2014 | pmid = 24511136 | pmc = 4033381 | doi = 10.1681/ASN.2013080904 }}</ref><ref>{{cite journal | vauthors = Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O'Shea JJ | display-authors = 6 | title = Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling | journal = Nature | volume = 467 | issue = 7318 | pages = 967–71 | date = October 2010 | pmid = 20962846 | pmc = 3108066 | doi = 10.1038/nature09447 | bibcode = 2010Natur.467..967G }}</ref><ref>{{cite journal | vauthors = McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ | title = TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology | journal = Nature Immunology | volume = 8 | issue = 12 | pages = 1390–7 | date = December 2007 | pmid = 17994024 | doi = 10.1038/ni1539 | s2cid = 33725832 }}</ref> The production of IL-22 in this subset of T_h17 cells is regulated by AhR and T_reg17 cells are depend on activation of the transcription factor Stat3. In a steady state, TGF-beta and AhR ligands induce low expression of IL-22 along with high expression of AhR, c-MAF, IL-10, and IL-21 that might play a protective role in cell regeneration and host microbiome homeostasis.

T_h17 cells mediate the regression of tumors in mice,<ref>{{cite journal | vauthors = Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A, Paulos CM, Palmer DC, Touloukian CE, Ptak K, Gattinoni L, Wrzesinski C, Hinrichs CS, Kerstann KW, Feigenbaum L, Chan CC, Restifo NP | display-authors = 6 | title = Tumor-specific Th17-polarized cells eradicate large established melanoma | journal = Blood | volume = 112 | issue = 2 | pages = 362–73 | date = July 2008 | pmid = 18354038 | pmc = 2442746 | doi = 10.1182/blood-2007-11-120998 }}</ref><ref>{{cite journal | vauthors = Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, Hwu P, Restifo NP, Overwijk WW, Dong C | display-authors = 6 | title = T helper 17 cells promote cytotoxic T cell activation in tumor immunity | journal = Immunity | volume = 31 | issue = 5 | pages = 787–98 | date = November 2009 | pmid = 19879162 | pmc = 2787786 | doi = 10.1016/j.immuni.2009.09.014 }}</ref> but were also found to promote tumor formation induced by colonic inflammation in mice.<ref>{{cite journal | vauthors = Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, Huso DL, Brancati FL, Wick E, McAllister F, Housseau F, Pardoll DM, Sears CL | display-authors = 6 | title = A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses | journal = Nature Medicine | volume = 15 | issue = 9 | pages = 1016–22 | date = September 2009 | pmid = 19701202 | pmc = 3034219 | doi = 10.1038/nm.2015 }}</ref> Like other T helper cells, T_h17 cells closely interact with B cells in response to pathogens. T_h17 cells are involved in B cell recruitment through CXCL13 chemokine signaling, and T_h17 activity may encourage antibody production.<ref>{{cite journal | vauthors = Crome SQ, Wang AY, Levings MK | title = Translational mini-review series on Th17 cells: function and regulation of human T helper 17 cells in health and disease | journal = Clinical and Experimental Immunology | volume = 159 | issue = 2 | pages = 109–19 | date = February 2010 | pmid = 19912252 | pmc = 2810379 | doi = 10.1111/j.1365-2249.2009.04037.x }}</ref>

T_reg17 cells regulate the function of T_h17 cells that are important role in the host defense against fungal and bacterial pathogens and participate in the pathogenesis of multiple inflammatory and autoimmune disorders. Selective deletion of Stat3 caused spontaneous severe colitis because of the lack of T_reg17 cells and increase in pathogenic T_h17 cells. The mechanism of T_reg17 cell action is expression of chemokine receptor CCR6, which facilitates trafficking into areas of T_h17 inflammation. This is also seen in human disease such glomerulonephritis (GN) in the kidney. Conversion of pathogenic T_h17 cells ''in vivo'' at the conclusion of an inflammatory disease process by TGF-β results in the generation of T_reg17 like cells.<ref>{{cite journal | vauthors = Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limón P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S, Flavell RA | display-authors = 6 | title = Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation | journal = Nature | volume = 523 | issue = 7559 | pages = 221–5 | date = July 2015 | pmid = 25924064 | pmc = 4498984 | doi = 10.1038/nature14452 | bibcode = 2015Natur.523..221G }}</ref> There is also conservation across species of T_reg17 cells.

== In disease == The dysregulation of T_h17 and switch to Th17 pathogenic phenotype cells have been associated with autoimmune disorders and inflammation. In the case of autoimmune disorders, T_h17 cell over activation can cause an inappropriate amount of inflammation, like in the case of rheumatoid arthritis. T_h17 cells have also been shown to be necessary for maintenance of mucosal immunity. In HIV, the loss of T_h17 cell populations can contribute to chronic infection.

=== Role in autoimmune disorders === T_h17 cells, particularly auto-specific T_h17 cells, are associated with autoimmune disease such as multiple sclerosis, rheumatoid arthritis, and psoriasis.<ref name="pmid23459074"/> T_h17 overactivation against autoantigen will cause type 3 immune complex and complement-mediated hypersensitivity. Rheumatoid arthritis or Arthus reaction belong to this category.<ref name="Harrington2005">{{cite journal | vauthors = Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT | title = Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages | journal = Nature Immunology | volume = 6 | issue = 11 | pages = 1123–32 | date = November 2005 | pmid = 16200070 | doi = 10.1038/ni1254 | s2cid = 11717696 }}</ref> Apart from autoantigen reactivity, T_h17 cells' inherent biology of low end MAP kinases signalling, especially Erk1/2 and p38, help their survival by refusing activation induced cell death (AICD).<ref>{{cite journal | vauthors = Peroumal D, Abimannan T, Tagirasa R, Parida JR, Singh SK, Padhan P, Devadas S | title = Inherent low Erk and p38 activity reduce Fas Ligand expression and degranulation in T helper 17 cells leading to activation induced cell death resistance | journal = Oncotarget | volume = 7 | issue = 34 | pages = 54339–54359 | date = August 2016 | pmid = 27486885 | pmc = 5342346 | doi = 10.18632/oncotarget.10913 | url = https://www.oncotarget.com/article/10913/text/ }}</ref> Together, excessive activity against autoantigen and prolonged existence of T_h17 cells have deleterious consequence in autoimmune disease like Rheumatoid arthritis.<ref>{{cite journal | vauthors = Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT | title = Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages | journal = Nature Immunology | volume = 6 | issue = 11 | pages = 1123–32 | date = November 2005 | pmid = 16200070 | doi = 10.1038/ni1254 | s2cid = 11717696 | url = https://www.nature.com/articles/ni1254 | url-access = subscription }}</ref>

Bone erosion caused by mature osteoclast cells is common in patients with rheumatoid arthritis. Activated T helper cells such as T_h1, T_h2, and T_h17 are found in the synovial cavity during the time of inflammation due to rheumatoid arthritis. The known mechanisms associated with the differentiation of osteoclast precursors into mature osteoclasts involve the signaling molecules produced by immune-associated cells, as well as the direct cell to cell contact of osteoblasts and osteoclast precursors. However, it has been suggested that T_h17 can also play a more major role in osteoclast differentiation via cell to cell contact with osteoclast precursors.<ref>{{cite journal | vauthors = Fumoto T, Takeshita S, Ito M, Ikeda K | title = Physiological functions of osteoblast lineage and T cell-derived RANKL in bone homeostasis | journal = Journal of Bone and Mineral Research | volume = 29 | issue = 4 | pages = 830–42 | date = April 2014 | pmid = 24014480 | doi = 10.1002/jbmr.2096 | s2cid = 32207557 | doi-access = }}</ref><ref>{{cite journal | vauthors = Won HY, Lee JA, Park ZS, Song JS, Kim HY, Jang SM, Yoo SE, Rhee Y, Hwang ES, Bae MA | display-authors = 6 | title = Prominent bone loss mediated by RANKL and IL-17 produced by CD4+ T cells in TallyHo/JngJ mice | journal = PLOS ONE | volume = 6 | issue = 3 | article-number = e18168 | date = March 2011 | pmid = 21464945 | pmc = 3064589 | doi = 10.1371/journal.pone.0018168 | bibcode = 2011PLoSO...618168W | doi-access = free }}</ref>

T_h17 cells may contribute to the development of late phase asthmatic response due to its increases in gene expression relative to T_reg cells.<ref name="pmid24991220">{{cite journal | vauthors = Singh A, Yamamoto M, Ruan J, Choi JY, Gauvreau GM, Olek S, Hoffmueller U, Carlsten C, FitzGerald JM, Boulet LP, O'Byrne PM, Tebbutt SJ | display-authors = 6 | title = Th17/Treg ratio derived using DNA methylation analysis is associated with the late phase asthmatic response | journal = Allergy, Asthma, and Clinical Immunology | volume = 10 | issue = 1 | page = 32 | date = 24 June 2014 | pmid = 24991220 | pmc = 4078401 | doi = 10.1186/1710-1492-10-32 | doi-access = free }}</ref>

=== Contribution of T_h17 cells in HIV pathogenesis === The depletion of T_h17 cell populations in the intestine disrupts the intestinal barrier, increases levels of movement of bacteria out of the gut through microbial translocation, and contributes to chronic HIV infection and progression to AIDS.<ref name="Favre e1000295">{{cite journal | vauthors = Favre D, Lederer S, Kanwar B, Ma ZM, Proll S, Kasakow Z, Mold J, Swainson L, Barbour JD, Baskin CR, Palermo R, Pandrea I, Miller CJ, Katze MG, McCune JM | display-authors = 6 | title = Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection | journal = PLOS Pathogens | volume = 5 | issue = 2 | article-number = e1000295 | date = February 2009 | pmid = 19214220 | pmc = 2635016 | doi = 10.1371/journal.ppat.1000295 | doi-access = free }}</ref> Microbial translocation results in bacteria moving from out of the gut lumen, into the lamina propria, to the lymph nodes, and beyond into non-lymphatic tissues. It can cause the constant immune activation seen through the body in the late stages of HIV. Increasing Th17 cell populations in the intestine has been shown to be both an effective treatment as well as possibly preventative.<ref name="Pallikkuth e1003471">{{cite journal | vauthors = Pallikkuth S, Micci L, Ende ZS, Iriele RI, Cervasi B, Lawson B, McGary CS, Rogers KA, Else JG, Silvestri G, Easley K, Estes JD, Villinger F, Pahwa S, Paiardini M | display-authors = 6 | title = Maintenance of intestinal Th17 cells and reduced microbial translocation in SIV-infected rhesus macaques treated with interleukin (IL)-21 | journal = PLOS Pathogens | volume = 9 | issue = 7 | article-number = e1003471 | date = 2013-07-04 | pmid = 23853592 | pmc = 3701718 | doi = 10.1371/journal.ppat.1003471 | doi-access = free }}</ref>

Although all CD4+ T cells gut are severely depleted by HIV, the loss of intestinal T_h17 cells in particular has been linked to symptoms of chronic, pathogenic HIV and SIV infection. Microbial translocation is a major factor that contributes to chronic inflammation and immune activation in the context of HIV.<ref>{{cite journal | vauthors = Fung TC, Artis D, Sonnenberg GF | title = Anatomical localization of commensal bacteria in immune cell homeostasis and disease | journal = Immunological Reviews | volume = 260 | issue = 1 | pages = 35–49 | date = July 2014 | pmid = 24942680 | pmc = 4216679 | doi = 10.1111/imr.12186 }}</ref> In non-pathogenic cases of SIV, microbial translocation is not observed. Th17 cells prevent severe HIV infection by maintaining the intestinal epithelial barrier during HIV infection in the gut.<ref name="Pallikkuth e1003471"/> Because of their high levels of CCR5 expression, the coreceptor for HIV, they are preferentially infected and depleted.<ref>{{cite journal | vauthors = Bixler SL, Mattapallil JJ | title = Loss and dysregulation of Th17 cells during HIV infection | journal = Clinical & Developmental Immunology | volume = 2013 | article-number = 852418 | date = 2013-01-01 | pmid = 23762098 | pmc = 3677006 | doi = 10.1155/2013/852418 | doi-access = free }}</ref> Thus, it is through Th17 cell depletion that microbial translocation occurs.

Additionally, the loss of T_h17&nbsp;cells in the intestine leads to a loss of balance between inflammatory T_h17&nbsp;cells and T_reg&nbsp;cells, their anti-inflammatory counterparts. Because of their immunosuppressive properties, they are thought to decrease the anti-viral response to HIV, contributing to pathogenesis. There is more T_reg activity compared to T_h17 activity, and the immune response to the virus is less aggressive and effective.<ref name="Favre e1000295"/>

Revitalizing T_h17&nbsp;cells has been shown to decrease symptoms of chronic infection, including decreased inflammation, and results in improved responses to highly active anti-retroviral treatment (HAART). This is an important finding—microbial translocation general results in unresponsiveness to HAART. Patients continue to exhibit symptoms and do not show as reduced a viral load as expected.<ref>{{cite journal | vauthors = Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG, Douek DC | display-authors = 6 | title = Microbial translocation is a cause of systemic immune activation in chronic HIV infection | journal = Nature Medicine | volume = 12 | issue = 12 | pages = 1365–71 | date = December 2006 | pmid = 17115046 | pmc = 1717013 | doi = 10.1038/nm1511 }}</ref> In an SIV-rhesus monkey model, it was found that administering IL-21, a cytokine shown to encourage Th17 differentiation and proliferation, decreases microbial translocation by increasing Th17 cell populations.<ref name="Pallikkuth e1003471"/> It is hopeful that more immunotherapies targeting Th17 cells could help patients who do not respond well to HAART.

In addition, T_h17&nbsp;cells are cellular reservoirs of virus in patients submitted to antiretroviral therapy (in addition to the major cell sanctuary which are follicular Th cells) and should contribute to the latency of the HIV infection.<ref>{{cite journal |last1=Gosselin |first1=Annie |last2=Monteiro |first2=Patricia |last3=Chomont |first3=Nicolas |last4=Diaz-Griffero |first4=Felipe |last5=Said |first5=Elias A. |last6=Fonseca |first6=Simone |last7=Wacleche |first7=Vanessa |last8=El-Far |first8=Mohamed |last9=Boulassel |first9=Mohamed-Rachid |last10=Routy |first10=Jean-Pierre |last11=Sekaly |first11=Rafick-Pierre |last12=Ancuta |first12=Petronela |title=Peripheral Blood CCR4+CCR6+ and CXCR3+CCR6+ CD4+ T Cells Are Highly Permissive to HIV-1 Infection |journal=The Journal of Immunology |date=30 December 2009 |volume=184 |issue=3 |pages=1604–1616 |doi=10.4049/jimmunol.0903058|pmid=20042588 |pmc=4321756 }}</ref>

=== Contribution of T_h17 cells in tuberculosis === Recent studies have recognized that T_h17&nbsp;T cells may play a role in tuberculosis. Polyfunctional T cells with T_h17 T&nbsp;cell features are depleted in individuals that progress to active TB after infection. In freshly resected lung tissue, from individuals with active or previous TB, CD4⁺ T&nbsp;cells have been identified that are enriched for IL-17–producing cells, including antigen specific T&nbsp;cells.<ref>{{cite journal | vauthors = Ogongo P, Tezera LB, Ardain A, Nhamoyebonde S, Ramsuran D, Singh A, Ng'oepe A, Karim F, Naidoo T, Khan K, Dullabh KJ, Fehlings M, Lee BH, Nardin A, Lindestam Arlehamn CS, Sette A, Behar SM, Steyn AJ, Madansein R, Kløverpris HN, Elkington PT, Leslie A | display-authors = 6 | title = Tissue-resident-like CD4+ T cells secreting IL-17 control Mycobacterium tuberculosis in the human lung | journal = The Journal of Clinical Investigation | volume = 131 | issue = 10 | date = May 2021 | pmid = 33848273 | pmc = 8121523 | doi = 10.1172/JCI142014 }}</ref> A cohort study conducted in Peru demonstrated that individuals who progressed to develop active TB after infection were depleted in T_h17 functioning T&nbsp;cells.<ref>{{cite journal | vauthors = Nathan A, Beynor JI, Baglaenko Y, Suliman S, Ishigaki K, Asgari S, Huang CC, Luo Y, Zhang Z, Lopez K, Lindestam Arlehamn CS, Ernst JD, Jimenez J, Calderón RI, Lecca L, Van Rhijn I, Moody DB, Murray MB, Raychaudhuri S | display-authors = 6 | title = Multimodally profiling memory T cells from a tuberculosis cohort identifies cell state associations with demographics, environment and disease | journal = Nature Immunology | volume = 22 | issue = 6 | pages = 781–793 | date = June 2021 | pmid = 34031617 | pmc = 8162307 | doi = 10.1038/s41590-021-00933-1 }}</ref>

=== Role of vitamin D === The active form of vitamin D (1,25-Dihydroxyvitamin D3) has been found to 'severely impair' <ref>{{cite journal | vauthors = Chang SH, Chung Y, Dong C | title = Vitamin D suppresses T_h17 cytokine production by inducing C/EBP homologous protein (CHOP) expression | journal = The Journal of Biological Chemistry | volume = 285 | issue = 50 | pages = 38751–5 | date = December 2010 | pmid = 20974859 | pmc = 2998156 | doi = 10.1074/jbc.C110.185777 | doi-access = free }}</ref> production of the IL-17 and IL-17F cytokines by T_h17 cells. Thus, active form of vitamin D is a direct inhibitor for T_h17 differentiation. In this way, oral administration of vitamin D3 was proposed to be a promising tool for the treatment of Th17-mediated diseases.<ref>{{cite journal | vauthors = Chang JH, Cha HR, Lee DS, Seo KY, Kweon MN | title = 1,25-Dihydroxyvitamin D3 inhibits the differentiation and migration of T(H)17 cells to protect against experimental autoimmune encephalomyelitis | journal = PLOS ONE | volume = 5 | issue = 9 | article-number = e12925 | date = September 2010 | pmid = 20886077 | pmc = 2944871 | doi = 10.1371/journal.pone.0012925 | bibcode = 2010PLoSO...512925C | doi-access = free }}</ref> In young patients with asthma 1,25-Dihydroxyvitamin D3-treated dendritic cells significantly reduced the percentage of T_h17 cells, as well as IL-17 production.<ref>{{cite journal | vauthors = Hamzaoui A, Berraïes A, Hamdi B, Kaabachi W, Ammar J, Hamzaoui K | title = Vitamin D reduces the differentiation and expansion of Th17 cells in young asthmatic children | journal = Immunobiology | volume = 219 | issue = 11 | pages = 873–9 | date = November 2014 | pmid = 25128460 | doi = 10.1016/j.imbio.2014.07.009 }}</ref>

== History of research == Intensive research starting in 2004 in mouse models elucidated its transcription factors and the cytokines that provoke differentiation.<ref name="Korn-et-al-2009">{{cite journal | issue=1 | volume=27 | year=2009 | journal=Annual Review of Immunology | issn=0732-0582 | publisher=Annual Reviews | pages=485–517 | last1=Korn | first1=Thomas | last2=Bettelli | first2=Estelle | last3=Oukka | first3=Mohamed | last4=Kuchroo | first4=Vijay K. | title=IL-17 and Th17 Cells | doi=10.1146/annurev.immunol.021908.132710 | pmid=19132915 | author4-link=Vijay Kuchroo | id=(VK ORCID: [http://orcid.org/0000-0001-7177-2110 0000-0001-7177-2110]. GS: [https://scholar.google.com/citations?user=h6h5FdoAAAAJ h6h5FdoAAAAJ])}}</ref>

== References == {{reflist|2}}

{{Lymphocytes}} {{Immune system}} {{Authority control}} {{Use dmy dates|date=December 2020}}

Category:T cells