T helper 17 cell
T helper 17 cells (Th17) 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 Th17s to differentiate actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces, but they have also been implicated in autoimmune and inflammatory disorders. The loss of Th17 cell populations at mucosal surfaces has been linked to chronic inflammation and microbial translocation.
Transforming growth factor beta (TGF-β), interleukin 6 (IL-6), interleukin 21 (IL-21) and interleukin 23 (IL-23) contribute to Th17 formation in mice and humans. Key factors in the differentiation of Th17 cells are signal transducer and the activator of transcription 3 (Stat3) and retinoic acid receptor-related orphan receptors gamma (RORγ) and alpha (RORα). The Th17 cells can alter their differentiation program ultimately giving rise to either protective or pro-inflammatory pathogenic cells. The protective and non-pathogenic Th17 cells induced by IL-6 and TGF-β are termed as Treg17 cells. The pathogenic Th17 cells are induced by IL-23 and IL-1β. IL-21, produced by Th17 cells themselves, has also been shown to initiate an alternative route for the activation of Th17 populations. Both interferon gamma (IFNγ) and IL-4, the main stimulators of Th1 and Th2 differentiation, respectively, have been shown to inhibit Th17 differentiation.
Th17 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. Their main effector cytokines are IL-17A, IL-17F, IL-21, and IL-22. Th17 cells mediate the regression of tumors in mice, but were also found to promote tumor formation induced by colonic inflammation in mice. Like other T helper cells, Th17 cells closely interact with B cells in response to pathogens. Th17 cells are involved in B cell recruitment through CXCL13 chemokine signaling, and Th17 activity may encourage antibody production.
Th17 cells in disease
The dysregulation of Th17 cells has been associated with autoimmune disorders and inflammation. In the case of autoimmune disorders, Th17 cell over activation can cause an inappropriate amount of inflammation, like in the case of rheumatoid arthritis. Th17 cells have also been shown to be necessary for maintenance of mucosal immunity. In HIV, the loss of Th17 cell populations can contribute to chronic infection.
Role of Th17 cells in autoimmune disorders
Th17 cells, particularly auto-specific Th17 cells, are associated with autoimmune disease such as multiple sclerosis, rheumatoid arthritis, and psoriasis. Th17 overactivation against autoantigen will cause type 3 immune complex and complement-mediated hypersensitivity. Rheumatoid arthritis or Arthus reaction belong to this category.
Bone erosion caused by mature osteoclast cells is common in patients with rheumatoid arthritis. Activated T helper cells such as Th1, Th2, and Th17 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 Th17 can also play a more major role in osteoclast differentiation via cell to cell contact with osteoclast precursors.
Loss of Th17 cells in HIV pathogenesis
The depletion of Th17 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. Microbial translocation results in bacteria moving from out of the gut lumen, into the lamina propia, 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.
Although all CD4+ T cells gut are severely depleted by HIV, the loss of intestinal Th17 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. 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. Because of their high levels of CCR5 expression, the coreceptor for HIV, they are preferentially infected and depleted. Thus, it is through Th17 cell depletion that microbial translocation occurs.
Additionally, the loss of Th17 cells in the intestine leads to a loss of balance between inflammatory Th17 cells and Treg 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 Treg activity compared to Th17 activity, and the immune response to the virus is less aggressive and effective.
Revitalizing Th17 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. 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. It is hopeful that more immunotherapies targeting Th17 cells could help patients who do not respond well to HAART.
- Hartigan-O'Connor, Dennis J.; Hirao, Lauren A.; McCune, Joseph M.; Dandekar, Satya (2011-05-01). "Th17 cells and regulatory T cells in elite control over HIV and SIV". Current opinion in HIV and AIDS. 6 (3): 221–227. doi:10.1097/COH.0b013e32834577b3. ISSN 1746-6318. PMC . PMID 21399494.
- Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (Sep 2006). "The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells". Cell. 126 (6): 1121–33. doi:10.1016/j.cell.2006.07.035. PMID 16990136.
- Singh B, Schwartz JA, Sandrock C, Bellemore SM, Nikoopour E (2013). "Modulation of autoimmune diseases by interleukin (IL)-17 producing regulatory T helper (Th17) cells". Indian J Med Res. 138 (5): 591–4. PMC . PMID 24434314.
- Korn T, Bettelli E, Gao W, et al. (July 2007). "IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells". Nature. 448 (7152): 484–487. doi:10.1038/nature05970. PMID 17581588.
- Vautier, Simon; Sousa, Maria da Glória; Brown, Gordon D. "C-type lectins, fungi and Th17 responses". Cytokine & Growth Factor Reviews. 21 (6): 405–412. doi:10.1016/j.cytogfr.2010.10.001.
- José Francisco Zambrano-Zaragoza; Enrique Jhonatan Romo-Martínez; Ma. de Jesús Durán-Avelar; Noemí García-Magallanes; Norberto Vibanco-Pérez (Aug 2014). "Th17 Cells in Autoimmune and Infectious Diseases". Int J Inflam. 2014: 651503. doi:10.1155/2014/651503. PMC . PMID 25152827.
- Muranski P, Boni A, Antony PA, et al. (July 2008). "Tumor-specific Th17-polarized cells eradicate large established melanoma". Blood. 112 (2): 362–373. doi:10.1182/blood-2007-11-120998. PMC . PMID 18354038.
- Martin-Orozco N, Muranski P, Chung Y, et al. (November 2009). "T helper 17 cells promote cytotoxic T cell activation in tumor immunity". Immunity. 31 (5): 787–798. doi:10.1016/j.immuni.2009.09.014. PMC . PMID 19879162.
- Wu S, Rhee KJ, Albesiano E, et al. (September 2009). "A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses". Nature Medicine. 15 (9): 1016–1022. doi:10.1038/nm.2015. PMC . PMID 19701202.
- Crome, S Q; Wang, A Y; Levings, M K (2017-01-29). "Translational Mini-Review Series on Th17 Cells: Function and regulation of human T helper 17 cells in health and disease". Clinical and Experimental Immunology. 159 (2): 109–119. doi:10.1111/j.1365-2249.2009.04037.x. ISSN 0009-9104. PMC . PMID 19912252.
- Harrington, LE; Hatton, RD; Mangan, PR; Turner, Henrietta; Murphy, Theresa L; Murphy, Kenneth M; Weaver, Casey T (2005). "Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages". Nature Immunology. 6 (11): 1023–32. doi:10.1038/ni1254. PMID 16200070
- Fumoto, T; Takeshita, S; Ito, M; Ikeda, K (2013). "Physiological functions of osteoblast lineage and T cell-derived RANKL in bone homeostasis". J. Bone Miner. Res. 29 (4): 830–42. doi:10.1002/jbmr.2096. PMID 24014480.
- Won HY, Lee JA, Park ZS, Song JS, Kim HY, Jang SM, Yoo SE, Rhee Y, Hwang ES, Bae MA (2011). "Prominent bone loss mediated by RANKL and IL-17 produced by CD4+ T cells in TallyHo/JngJ mice". PLoS ONE. 6 (3): e18168. doi:10.1371/journal.pone.0018168. PMC . PMID 21464945.
- 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 (24 Jun 2014). "Th17/Treg ratio derived using DNA methylation analysis is associated with the late phase asthmatic response.". Allergy Asthma Clin Immunol. 10 (1): 32. doi:10.1186/1710-1492-10-32. PMC . PMID 24991220.
- Favre, David; Lederer, Sharon; Kanwar, Bittoo; Ma, Zhong-Min; Proll, Sean; Kasakow, Zeljka; Mold, Jeff; Swainson, Louise; Barbour, Jason D. (2009-02-13). "Critical Loss of the Balance between Th17 and T Regulatory Cell Populations in Pathogenic SIV Infection". PLoS Pathog. 5 (2): e1000295. doi:10.1371/journal.ppat.1000295. PMC . PMID 19214220.
- Pallikkuth, Suresh; Micci, Luca; Ende, Zachary S.; Iriele, Robin I.; Cervasi, Barbara; Lawson, Benton; McGary, Colleen S.; Rogers, Kenneth A.; Else, James G. (2013-07-04). "Maintenance of Intestinal Th17 Cells and Reduced Microbial Translocation in SIV-infected Rhesus Macaques Treated with Interleukin (IL)-21". PLoS Pathog. 9 (7): e1003471. doi:10.1371/journal.ppat.1003471. PMC . PMID 23853592.
- Fung, Thomas C.; Artis, David; Sonnenberg, Gregory F. (2014-07-01). "Anatomical localization of commensal bacteria in immune cell homeostasis and disease". Immunological Reviews. 260 (1): 35–49. doi:10.1111/imr.12186. ISSN 1600-065X. PMC . PMID 24942680.
- Bixler, Sandra L.; Mattapallil, Joseph J. (2013-01-01). "Loss and dysregulation of Th17 cells during HIV infection". Clinical & Developmental Immunology. 2013: 852418. doi:10.1155/2013/852418. ISSN 1740-2530. PMC . PMID 23762098.
- Brenchley, Jason M.; Price, David A.; Schacker, Timothy W.; Asher, Tedi E.; Silvestri, Guido; Rao, Srinivas; Kazzaz, Zachary; Bornstein, Ethan; Lambotte, Olivier (2006-12-01). "Microbial translocation is a cause of systemic immune activation in chronic HIV infection". Nature Medicine. 12 (12): 1365–1371. doi:10.1038/nm1511. ISSN 1078-8956. PMID 17115046.