T helper 17 cell

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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.[1] 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.

Differentiation[edit]

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).[2] Th17 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.[3] 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.[4] IL-21, produced by Th17 cells themselves, has also been shown to initiate an alternative route for the activation of Th17 populations.[5] Both interferon gamma (IFNγ) and IL-4, the main stimulators of Th1 and Th2 differentiation, respectively, have been shown to inhibit Th17 differentiation.[citation needed]

Function[edit]

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.[6] Their main effector cytokines are IL-17A, IL-17F, IL-21, and IL-22[7], 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, Th17 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 Th2 cells regulate eosinophils, basophils and mast cells, and Th1 cells regulate macrophages and monocytes.[8] Thus, three T helper cell subsets are able to influence myeloid part of the immune system, largely responsible for innate defense against pathogens.

Th17 cells mediate the regression of tumors in mice,[9][10] but were also found to promote tumor formation induced by colonic inflammation in mice.[11] 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.[12]

In disease[edit]

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 in autoimmune disorders[edit]

Th17 cells, particularly auto-specific Th17 cells, are associated with autoimmune disease such as multiple sclerosis, rheumatoid arthritis, and psoriasis.[7] Th17 overactivation against autoantigen will cause type 3 immune complex and complement-mediated hypersensitivity. Rheumatoid arthritis or Arthus reaction belong to this category.[13]

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.[14][15]

Th17 cells may contribute to the development of late phase asthmatic response due to its increases in gene expression relative to Treg cells.[16]

Loss of Th17 cells in HIV pathogenesis[edit]

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.[17] 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.[18]

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.[19] 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.[18] Because of their high levels of CCR5 expression, the coreceptor for HIV, they are preferentially infected and depleted.[20] 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.[17]

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.[21] 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.[18] It is hopeful that more immunotherapies targeting Th17 cells could help patients who do not respond well to HAART.

Role of Vitamin D[edit]

The active form of vitamin D (1,25-Dihydroxyvitamin D3) has been found to 'severely impair' [22] production of the IL-17 and IL-17F cytokines by Th17 cells. Thus, active form of vitamin D is a direct inhibitor for Th17 differentiation. In this way, oral administration of vitamin D3 was proposed to be a promising tool for the treatment of Th17-mediated diseases.[23] In young patients with asthma 1,25-Dihydroxyvitamin D3-treated dendritic cells significantly reduced the percentage of Th17 cells, as well as IL-17 production.[24]

References[edit]

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