High‐frequency vaccine‐induced CD8⁺ T cells specific for an epitope naturally processed during infection with Mycobacterium tuberculosis do not confer protection

Abstract

Relatively few MHC class I epitopes have been identified from M. tuberculosis, but during the late stage of infection CD8+ T-cell responses to these epitopes are often primed at an extraordinary high frequency. Although clearly available for recognition during infection, their role in resistance to mycobacterial infections still remain unclear. As an alternative to DNA and viral vaccination platforms, we have exploited a novel CD8+ T-cell-inducing adjuvant, CAF05 (DDA/TDB/Poly I:C), to prime high frequency CD8 responses to the immunodominant H2-Kb-restricted IMYNYPAM epitope contained in the vaccine antigen TB10.4/Rv0288/EsxH. We report that the amino acid C-terminal to this minimal epitope plays a decisive role in proteasomal cleavage and epitope priming. The primary structure of TB10.4 is suboptimal for proteasomal processing of the epitope and amino acid substitutions in the flanking region markedly increased epitope-specific CD8+ T-cell responses. One of the optimized sequences was contained in the closely related TB10.3/Rv3019c/EsxR antigen and when recombinantly expressed and administered in the CAF05 adjuvant, this antigen promoted very high CD8+ T-cell responses. This abundant T-cell response was functionally active but provided no protection against challenge, suggesting that CD8+ T-cells play a limited role in protection against M. tuberculosis in the mouse model.

Epitope‐specific CD4+, but not CD8+, T‐cell responses induced by recombinant influenza A viruses protect against Mycobacterium tuberculosis infection

“…Reduced direct contact of the TB10.4‐specific CD8 + T cells with M. tuberculosis ‐infected macrophages within the granuloma or relative differences in cytokine production compared to CD4 + T cells, may contribute to the lack of protection in PR8.TB10.4‐immunized mice. A similar lack of correlation between the induction of strong M. tuberculosis ‐specific CD8 + T‐cell responses and protective immunity has been reported for other experimental TB vaccines in mice . For example, stimulation of high levels of TB10.4 ‐ specific CD8 + T cells with peptide in a cationic adjuvant formulation also failed to protect against pulmonary TB .…”

Adenovirally-Induced Polyfunctional T Cells Do Not Necessarily Recognize the Infected Target: Lessons from a Phase I Trial of the AERAS-402 Vaccine

“…Similarly, Lindestrom et al . report the structure of TB10.4 limits effective proteosomal and epitope processing38. In any case, the determination and subsequent use of antigens associated with robust Mtb-specific CD8 + T cell responses might improve the ability of virally delivered vaccines to elicit epitopes displayed during the course of infection with Mtb.…”

The generation of T‐cell memory to protect against tuberculosis

“…In mice, BCG is a poor stimulator of CD8 + T‐cell responses compared with M. tuberculosis and this is the rationale for the development of vaccines targeting CD8 + T‐cell expansion . However, viral and subunit vaccines that lead to strong CD8 + T‐cell responses in mice did not improve protection against M. tuberculosis infection . Both these studies, however, used the immunodominant M. tuberculosis antigen, TB10.4, and TB10.4‐specific CD8 + T cells appear unable to recognize M. tuberculosis ‐infected macrophages, which suggests that M. tuberculosis may subvert the CD8 + T‐cell responses as a virulence strategy.…”