Promiscuous peptide of 16 kDa antigen linked to Pam2Cys protects against M tuberculosis by evoking enduring metnory T cell response

BCG has been administered globally for more than 75 years, yet tuberculosis (TB) continues to kill more than 2 million people annually. Further, BCG protects childhood TB but is quite inefficient in adults. This indicates that BCG fails to induce long-term protection. Hence there is a need to explore alternative vaccination strategies that can stimulate enduring T cell memory response. Dendritic cell based vaccination has attained extensive popularity following their success in various malignancies. In our previous study, we have established a novel and unique vaccination strategy against Mycobacterium tuberculosis (M. tb) and Salmonella typhimurium by utilizing infected macrophages (IM). In short-term experiments {30 days). substantial degree of protection was observed. However, remarkable difference was not observed in long-term studies (240 days) due to failure of the vaccine to generate long-lasting memory T cells. Hence, in the present study we employed T cell memory augmenting cytokines IL-1 +IL-6+ TN F-a: and IL-7+1L-1 5 for the induction of the enhancement of long-term protection by the vaccine. We co-administered the M. tb infected macrophages vaccine with IL-1 +IL-6+ TN F-a: (IM-1 .6.a:) and IL-7+1L-1 5 (IM-7.1 5). The mice were then rested for a reasonably large period (240 days) to study the bona fide T cell memory response before exposing them to aerosolized M. tb. IM-1.6.a: but not IM-7.1 5 significantly improved memory T cell response against M. tb, as evidenced by recall responses of memory T cells, expansion of both central as well as effector memory CD4 and CDS T cell pools, elicitation of mainly Th1 memory response, reduction in the mycobacterial load and alleviated lung pathology. Importantly, the protection induced by IM-1 .6.a: was significantly better than BCG. Thus, this study demonstrates that not only antigen-pulsed DCs can be successfully employed as vaccines against cancer and infectious diseases but also macrophages infected with M. tb can be utilized with great efficacy especially in protection against TB. Citation: Singh V, Jain S, Gowthaman U, Parihar P, Gupta P, et al. (2011) Co-Administration of IL-l+IL-6+ TNF-o: with Mycobacterium tuberculosis Infected Macrophages Vaccine Induces Better Protective T Cel l Memory than BCG. PLoS ONE 6(1): e16097. doi:10.1371/journal.pone.0016097 Editor: Leonardo A. Sechi, Universita di Sassari, Italy Received November 30, 2010; Accepted December 10, 2010; Published January 19, 2011 Copyright: © 201 1 Singh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the origina l author and source are credited. Funding: This study is supported by the Indian Council of Medical Resea rch (Grant Reference No. S/8/5/6/200S-ECD-I) and Department of Biotechnology (Grant Reference No. BT/PR6219/Med/ 14/762/ 2005), New Delhi, India. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. • E-mail: javed@imtech.res.in