CD8 T-cell immunity

A greater understanding of how the immune system responses to Mtb is needed to develop an effective vaccine. Although both CD4 and CD8 T cell responses are generated during infection, and their arrival into lungs effectively contains Mtb replication, CD4 T cells are thought to play a more important role in the protection. This is supported by the higher risk in AIDS patients to develop active tuberculosis, and the early mortality in experimental mice deficient in CD4 T cells [1]. In contrast, CD8 T cell’s role in the protective immunity is less appreciated. Nevertheless, evidence highlighting the importance of CD8 T cells are emerging. In non-human primate (NHP) studies, CD8 depletion compromised BCG-induced control [2], and their cytotoxicity functions were corelated with Mtb restriction in granulomas.

Although CD4 T cell mediated protection has shown to be indispensable, we hypothesized that CD8 T cells also played a crucial part against Mtb. The Behar lab has dedicated to understanding the roles CD8 T cells played during infection and made significant progresses that have implications for future vaccine design. Recently, we found CD8 T cells specific for TB10.44-11, a dominate epitope occurred in infection, didn’t efficiently recognize infected macrophages [3]. This may be the underlining mechanism that vaccines designed to induce strong Mtb-specific responses didn’t confer protection. We and others suggested that recognition of infected cells could be a criterion for screening vaccine candidates before clinical trial [4]. Moreover, we showed that to generate optimal CD8 T cell responses, CD4 T cells were essential. Through comparing Mtb-specific CD8 T cell responses in WT vs. MHC II KO mice, we revealed that helped CD8 T cells were effector cells with cytotoxicity functions. In contrast, helpless CD8 T cells were exhausted. Importantly, helped CD8 T cells mediated better Mtb control than helpless CD8 T cells. Since current vaccines are evaluated mainly on their ability to generate CD4 T cell immunity, we suggest that vaccines eliciting both CD4 and CD8 T cell responses are likely to be successful.

Currently, the Behar lab has identified a portion of polyclonal CD8 T cells do recognize infected cells [5]. We’re trying to understand the transcriptional signatures of CD8 T cells after recognizing infected cells, and to discover new antigens expressed by infected cells that are recognized. We believe these are important questions to tackle in order to uncover the role of CD8 T cells in protective immunity and to design better vaccines.

1. Mogues, T., et al., The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice. J Exp Med, 2001. 193(3): p. 271-80.
2. Chen, C.Y., et al., A critical role for CD8 T cells in a nonhuman primate model of tuberculosis. PLoS Pathog, 2009. 5(4): p. e1000392.
3. Yang, J.D., et al., Mycobacterium tuberculosis-specific CD4+ and CD8+ T cells differ in their capacity to recognize infected macrophages. PLoS Pathog, 2018. 14(5): p. e1007060.
4. Nyendak, M., et al., Adenovirally-Induced Polyfunctional T Cells Do Not Necessarily Recognize the Infected Target: Lessons from a Phase I Trial of the AERAS-402 Vaccine. Sci Rep, 2016. 6: p. 36355.
5. Patankar, Y.R., et al., Limited recognition of Mycobacterium tuberculosis-infected macrophages by polyclonal CD4 and CD8 T cells from the lungs of infected mice. Mucosal Immunol, 2020. 13(1): p. 140-148.