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

<div><p>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 <i>Mycobacterium tuberculosis</i> (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 <i>in vivo</i>. 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.</p></div

MAIT cells are not preferentially infected by HTLV-1.

<p>Proviral load in sorted CD4 T cells (closed circles) and MAIT cells (open circles) from three HTLV-1-infected subjects.</p

MAIT cells are reduced in HTLV-1 infection.

<p>Representative flow plots showing gating strategy and MAIT cell frequency in healthy controls and HTLV-infected individuals (A). Frequency of MAIT cells in healthy controls (n = 12) and HLTV-1 patients (n = 20) (B). Frequency of MAIT cells in asymptomatic (n = 10) and HAM/TSP (n = 10) HTLV-1 patients (C). ** indicates p < 0.001. The lines and whiskers represent the median and interquartile range respectively.</p

MAIT cells are functionally impaired in HTLV-1 infection.

<p>PBMCs were stimulated with <i>E</i>. <i>coli</i> for 24h at a MOI of 10 and Monensin was added during the last 6 hours before staining for surface antigens and intracellular staining for IFNγ. Representative flow plots of CD69 expression and IFNγ production by MAIT cells (CD3+ Vα7.2+ CD161+) from healthy controls and HTLV-1-infected individuals (A). Production of IFNγ by MAIT cells in healthy controls (n = 11) and HTLV-1-infected subjects (n = 17) (B). Production of IFNγ by MAIT cells in asymptomatic (n = 8), and HAM/TSP (n = 9) HTLV-1-infected subjects (C). CD69 expression by MAIT cells in healthy controls and HTLV-1-infected subjects (D). CD69 expression by MAIT cells in asymptomatic, and HAM/TSP HTLV-1-infected subjects (E). * indicates p <b>≤</b> 0.05 and ** indicates p < 0.01. The lines and whiskers represent the median and interquartile range respectively.</p

Associations between immune activation and HTLV-1 proviral load.

<p>Associations between proviral load and CD4 T cell (A), CD8 T cell (B), and MAIT cell (C) co-expression of CD38 and HLA-DR. Association between proviral load and MAIT cell frequency (D). Association between co-expression of CD38 and HLA-DR (E) and PD-1 expression (F) by MAIT cells and MAIT cell frequency.</p

Patients demographics.

<p>Patients demographics.</p

MAIT cells are activated in HTLV-1 infection.

<p>Co-expression of CD38 and HLA-DR by CD4 T cells in healthy controls (n = 12) and HLTV-1 patients (n = 20) (A). Co-expression of CD38 and HLA-DR by CD4 T cells in asymptomatic (n = 10) and HAM/TSP (n = 10) HTLV-1 patients (B). Co-expression of CD38 and HLA-DR by CD8 T cells in healthy controls and HLTV-1 patients (C). Co-expression of CD38 and HLA-DR by CD4 T cells in asymptomatic and HAM/TSP HTLV-1 patients (D). Co-expression of CD38 and HLA-DR by MAIT cells in healthy controls and HLTV-1 patients (E). Co-expression of CD38 and HLA-DR by MAIT cells in asymptomatic and HAM/TSP HTLV-1 patients (F). * indicates p <b>≤</b> 0.05, ** indicates p < 0.01, and *** indicates p < 0.001. The lines and whiskers represent the median and interquartile range respectively.</p