Immunization with a DNA Vaccine Cocktail Protects Mice Lacking CD4 Cells against an Aerogenic Infection withMycobacterium tuberculosis

Abstract

Tuberculosis (TB) is the most common opportunistic disease and a potentially fatal complication among immunocompromised individuals infected with human immunodeficiency virus (HIV). Effective vaccination

Multivalent TB vaccines targeting the esx gene family generate potent and broad cell-mediated immune responses superior to BCG

“…29,30,44,[51][52][53] These data highlight the importance of a vaccine that can induce optimal activation of both CD8 and CD4 T cells which could be the cornerstone for protective immunity against TB. In these studies we observe that compared with naïve animals and the BCG vaccine group, the RSQ15 vaccine induced relatively high levels of multifunctional CD4 T cells expressing dual IFN-γ and TNF-α after immunization, while esxV, esxU, esxS, esxQ, esxH, and esxR induced potent CD8 T cells secreting dual IFN-γ/TNF-α.…”

“…3). Given the importance of multifunctional CD4 and CD8 T cell immunity as an integral component of antimycobacterial immunity, 29,30 we measured the ability of vaccineinduced Ag-specific T cell populations to secrete both IFN-γ and TNF-α in response to ex vivo Ag-specific pooled peptide stimulation 1 wk after the last immunization. Our gating strategy of intracellular cytokine flow-cytometry analysis is depicted in Figure 3A.…”

Next generation: tuberculosis vaccines that elicit protective CD8+T cells

“…A combination of these approaches may be necessary to obtain clinically significant long-lived protective efficacy for DNA vaccines in humans. [103], suggesting that it may be possible to develop effective M. tuberculosis vaccines in HIV-infected populations. By contrast, DNA vaccines encoding mycobacterial antigens Ag85A, Ag85B and PstS3 from M. tuberculosis were ineffective in mice lacking CD4 + T cells [104].…”

Mycobacterium tuberculosis-Specific CD8+ T Cells and Their Role in Immunity

“…Finally, CFP10-specific CD8 + T cells were detected at frequencies as high as 1/700 total CD8 + T cells, suggesting that CFP10 can be an immunodominant antigen in people. A follow-up study by Shams et al defined a 15mer peptide (CFP10 [71][72][73][74][75][76][77][78][79][80][81][82][83][84][85], which contains at least two distinct epitopes, each one that can be presented by class I and II MHC to both CD8 + and CD4 + T cells, respectively (147). The promiscuity of these epitopes for different alleles of class I and class II MHC proteins may explain why nearly 100% of people with latent M. tuberculosis infection recognize CFP10.…”

“…CD4 −/− mice: The increased susceptibility of CD4 −/− mice to M. tuberculosis is cited as evidence for the importance of CD4 + T cells for immunity (77). Consequently, the ability of DNA vaccination to prolong survival and decrease bacterial load after aerosol M. tuberculosis infection in CD4 −/− mice is cited as evidence that class I MHC-restricted CD8 + T cells elicited by DNA immunization can mediate host protection (78). However, CD4 −/− mice have class II MHC-restricted CD4 − T cells (79;80).…”