gammadeltaT cells drive myeloid-derived suppressor cell-mediated CD8+ T cell exhaustion in hepatitis B virus-induced immunotolerance #MMPMID25015833
Kong X; Sun R; Chen Y; Wei H; Tian Z
J Immunol 2014[Aug]; 193 (4): 1645-53 PMID25015833show ga
The mechanisms of liver hepatitis B virus (HBV)-induced systemic immune tolerance are still elusive, and the role of gammadeltaT cells has not yet been described. We examined the function of gammadeltaT cells in HBV-carrier mice--immunocompetent mice with plasmid-mediated persistent HBV expression in the liver. In this study, we found that gammadeltaT cell deficiency led to a break in HBV-induced tolerance and subsequent recovery of hepatic HBV-specific CD8(+) T cells. Of interest, IL-17(-/-) mice phenocopied TCRdelta(-/-) mice in terms of losing HBV persistence, and adoptive transfer of gammadeltaT cells restored HBV-persistent expression in TCRdelta(-/-) mice. We further observed that hepatic CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs) play a major role in this mechanism, as they were significantly reduced in both HBV-carrier TCRdelta(-/-) and IL-17(-/-) mice. MDSC numbers also recovered after adoptive transfer of gammadeltaT cells, particularly Vgamma4(+) T cells. Furthermore, anti-Gr1-mediated MDSC depletion in HBV-carrier mice accelerated HBV elimination from the host, whereas MDSCs transferred to gammadeltaT cell-deficient mice restored HBV-induced tolerance. Accordingly, inhibition of MDSCs by the arginase-1 inhibitor norNOHA enhanced the number of HBV-specific CD8(+) T cells and promoted HBV clearance. We also observed enhanced CD8(+) T cell number with a notable decline of MDSCs in TCRdelta(-/-) mice compared with wild-type mice during the recombinant adeno-associated virus/HBV1.3 virus infection. Importantly, HBV-carrier TCRdelta(-/-) mice not only exhibited increased anti-HBV CD8(+) T cells but also markedly reduced MDSCs. Overall, the current study reveals that gammadeltaT cells play a previously unrecognized regulatory role in liver tolerance by mobilizing MDSC infiltration to the liver, leading to MDSC-mediated CD8(+) T cell exhaustion.
J+Immunol 2014 ; 193 (4): 1645-53
