T helper 17 cell

Differentiation

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). 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 Treg17 cells. The pathogenic T_h17 cells are induced by IL-23 and IL-1β. IL-21, produced by T_h17 cells themselves, has also been shown to initiate an alternative route for the activation of T_h17 populations. 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.

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. Their main effector cytokines are IL-17A, IL-17F, IL-21, and IL-22. T_h17 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, 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.

Th17 cells in disease

The dysregulation of T_h17 cells has 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 of Th17 cells 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. T_h17 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.

T_h17 cells may contribute to the development of late phase asthmatic response due to its increases in gene expression relative to Treg cells.

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.