MAIT cells are reduced in frequency and functionally impaired in human T lymphotropic virus type 1 infection: Potential clinical implications

Abstract

HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is unclear why a minority of infected subjects develop HAM/TSP. The cellular immune response has been implicated in the development of inflammatory alterations in these patients; however the pathogenic mechanisms for disease progression remain unclear. Furthermore, HTLV-1-infected individuals have an increase incidence of Mycobacterium tuberculosis (Mtb) infection, suggesting that immunological defect are associated with HTLV-1 infection. Evidence suggests an important role for Mucosal-associated invariant T (MAIT) cells in the early control of Mtb infection. Chronic viral infections like HIV and HCV have been associated with decreased frequency and functionality of MAIT cells. We hypothesized that HTLV-1 infection is associated with similar perturbations in MAIT cells. We investigated MAIT cell frequency, phenotype, and function by flow cytometry in a cohort of 10 asymptomatic and 10 HAM/TSP HTLV-1 infected patients. We found that MAIT cells from HTLV-1-infected subjects were reduced and showed high co-expression of the activation markers CD38 and HLA-DR but normal levels of CCR6 and CD127. MAIT cells had a lower expression of the transcription factor PLZF in HAM/TSP patients. Unlike Tax-specific CD8+T cells, which are hyperfunctional, MAIT cells from HTLV-1-infected subjects had a poor IFNγ response following antigen stimulation. MAIT cell perturbations in HTLV-1 infection were not associated with HTLV-1 proviral load and MAIT cells were not infected by HTLV-1 in vivo. Rather, MAIT cells loss was associated with immune activation. Overall, our results do not support a role for MAIT cells in HAM/TSP pathogenesis but reduced numbers of MAIT cells, together with their poor functionality, could contribute to the increased susceptibility of HTLV-1-infected individuals to other infectious agents.

Loss of Circulating Mucosal-Associated Invariant T Cells in Common Variable Immunodeficiency Is Associated with Immune Activation and Loss of Eomes and PLZF

“…The remaining MAIT cells had an elevated expression of activation markers, low expression of CCR6, and showed a poor IFN-g response following in vitro stimulation with E. coli. Activation and loss of MAIT cells in CVID is similar to what has been described for chronic viral infections such as HIV (27,28), human T cell leukemia virus type 1 (29), and hepatitis C virus (40). Loss of MAIT cells has also been reported in cystic fibrosis (45), a genetic condition associated with chronic bacterial infections.…”

“…In the mouse, MAIT cells have been reported to require B cells and commensal gut flora for expansion and acquisition of an effector phenotype (25), whereas in humans, MAIT cells gain some of their innate-like antimicrobial properties before birth in the mucosa (26). In HIV type 1 and human T cell leukemia virus type 1 infections, MAIT cells are reduced in number and display impaired functionality in response to bacterial stimulation (27)(28)(29). Microbial translocation is now recognized to have a major role in HIV immuno-pathogenesis, and recent evidence suggests that microbial translocation could be responsible for CD4 + T cell exhaustion in CVID patients (30).…”

MAIT cells and viruses

“…In patients with HTLV‐I‐associated myelopathy/tropical spastic paraparesis, decreased expression of PLZF was noted. MAIT cell numbers were not associated with viral load and MAIT cells were not infected by HTLV‐1 …”

“…MAIT cells are also depleted from the blood and show reduced functionality in patients infected with HTLV‐1 . Increased expression of activation markers was seen, but the cells had reduced ability to produce interferon‐γ; similar to HIV infection, the frequency of MAIT cells in blood was inversely correlated with their expression of activation markers . In patients with HTLV‐I‐associated myelopathy/tropical spastic paraparesis, decreased expression of PLZF was noted.…”

“…MAIT cell numbers were not associated with viral load and MAIT cells were not infected by HTLV-1. 67 In addition to blood-borne and chronic infections, where there is now quite a large amount of observational data in cohorts, there is also recent data on acute infections, dengue and influenza virus. Two papers have studied patients infected with influenza (pandemic H1N1 and H7N9) and both showed an inverse correlation between MAIT frequencies and severity of disease.…”