T helper 17 cell

T helper 17 cells (T_h17) are a subset of pro-inflammatory

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.[8] Their main effector cytokines are IL-17A, IL-17F, IL-21, and IL-22,^[9] 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.^[10] 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.^[11]

T_reg17 cells produce IL-17 and IL-10 and low level of IL-22 and suppress autoimmune and other immune responses. CD4⁺ T cells polarized with IL-23 and IL-6 are pathogenic upon adoptive transfer in

T_h17 cells mediate the regression of tumors in mice,[18]^[19] but were also found to promote tumor formation induced by colonic inflammation in mice.^[20] 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.^[21]

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

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.^[9] T_h17 overactivation against autoantigen will cause type 3 immune complex and complement-mediated hypersensitivity. Rheumatoid arthritis or Arthus reaction belong to this category.^[23] 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).^[24] Together, excessive activity against autoantigen and prolonged existence of T_h17 cells have deleterious consequence in autoimmune disease like Rheumatoid arthritis.^[25]

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.^[26][27]

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.^[28]

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.^[29] 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.^[30]

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.^[31] 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.^[30] Because of their high levels of CCR5 expression, the coreceptor for HIV, they are preferentially infected and depleted.^[32] Thus, it is through Th17 cell depletion that microbial translocation occurs.

Additionally, the loss of T_h17 cells in the intestine leads to a loss of balance between inflammatory T_h17 cells and T_reg 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.^[29]

Revitalizing T_h17 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.^[33] 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.^[30] It is hopeful that more immunotherapies targeting Th17 cells could help patients who do not respond well to HAART.

In addition, T_h17 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.^[34]

Contribution of T_h17 cells in tuberculosis

Recent studies have recognized that T_h17 T cells may play a role in tuberculosis. Polyfunctional T cells with T_h17 T 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 cells have been identified that are enriched for IL-17–producing cells, including antigen specific T cells.^[35] A cohort study conducted in Peru demonstrated that individuals who progressed to develop active TB after infection were depleted in T_h17 functioning T cells.^[36]

Role of vitamin D

The active form of