Development of genetically engineered iNKT cells expressing TCRs specific for the M. tuberculosis 38-kDa antigen

Zhen-Min Jiang, Wei Luo, Qian Wen, Su-Dong Liu, Pei-Pei Hao, Chao-Ying Zhou, Ming-Qian Zhou, Li Ma, Jiang, Zhen-Min, Luo, Wei, Wen, Qian, Liu, Su-Dong, Hao, Pei-Pei, Zhou, Chao-Ying, Zhou, Ming-Qian, Ma, Li

The invariant natural killer T (iNKT) cell has been shown to play a central role in early stages immune responses against Mycobacterium tuberculosis (Mtb) infection, which become nonresponsive (anergic) and fails to control the growth of Mtb in patients with active tuberculosis. Enhancement of iNKT cell responses to Mtb antigens can help to resist infection. In the present study, an Mtb 38-kDa antigen-specific T cell receptor (TCR) was isolated from human CD8(+) T cells stimulated by 38-kDa antigen in vitro, and then transduced into primary iNKT cells by retrovirus vector. The TCR gene-modified iNKT cells are endowed with new features to behave as a conventional MHC class I restricted CD8(+) T lymphocyte by displaying specific antigen recognition and anti-Mtb antigen activity in vitro. At the same time, the engineered iNKT cells retaining its original capacity to be stimulated proliferation by non-protein antigens α-Gal-Cer. This work is the first attempt to engineer iNKT cells by exogenous TCR genes and demonstrated that iNKT cell, as well as CD4(+) and CD8(+) T cells, can be genetically engineered to confer them a defined and alternative specificity, which provides new insights into TCR gene therapy for tuberculosis patients, especially those infected with drug-resistant Mtb.