Abstract
Suppression of CD8+ T cell activation is a critical mechanism used by Mycobacterium tuberculosis (MTB) to escape protective host immune responses. PPE38 belongs to the unique PPE family of MTB and in our previous study, PPE38 protein was speculated to participate in manipulating macrophage MHC class I pathway. To test this hypothesis, the function of mycobacterial PPE38 protein was assessed here using macrophage and mouse infection models. Decreased amount of MHC class I was observed on the surface of macrophages infected with PPE38-expressing mycobacteria. The transcript of genes encoding MHC class I was also inhibited by PPE38. After infection of C57BL/6 mice with Mycobacterium smegmatis expressing PPE38 (Msmeg-PPE38), decreased number of CD8+ T cells was found in spleen, liver, and lungs through immunohistochemical analysis, comparing to the control strain harboring empty vector (Msmeg-V). Consistently, flow cytometry assay showed that fewer effector/memory CD8+ T cells (CD44highCD62Llow) were activated in spleen from Msmeg-PPE38 infected mice. Moreover, Msmeg-PPE38 confers a growth advantage over Msmeg-V in C57BL/6 mice, indicating an effect of PPE38 to favor mycobacterial persistence in vivo. Overall, this study shows a unique biological function of PPE38 protein to facilitate mycobacteria to escape host immunity, and provides hints for TB vaccine development.
Highlights
Tuberculosis (TB) is an ancient disease caused by Mycobacterium tuberculosis (MTB), a pathogen that infects one-third of the world’s population
Based on our previous data, which showed that the major histocompatibility complex (MHC) class I pathway proteins TAP1 and TAP2 were significantly downregulated by PPE38 (Wang et al, 2013), we hypothesized that PPE38 might play a role in suppressing MHC class I expression
I in infected macrophages was inhibited by the Mycobacterium PPE38 protein, which in turn influenced the numbers of CD8+ T cells
Summary
Tuberculosis (TB) is an ancient disease caused by Mycobacterium tuberculosis (MTB), a pathogen that infects one-third of the world’s population. Antigen processing (TAP)-1(−/−) or CD8 (−/−) knockout mice with disruptions of the MHC class I antigen processing pathway or/and functional CD8+ T cells are more susceptible to MTB infection (Flynn et al, 1992; Behar et al, 1999; Sousa et al, 2000; Turner et al, 2001; Urdahl et al, 2003) Both murine and human CD8+ T cells could be activated by mycobacterial antigens (Ags) (Stenger et al, 1997; Lalvani et al, 1998; Kamath et al, 2004, 2006; Irwin et al, 2005; Woodworth et al, 2011). In TB patients, CD8+ T cells were found in granulomas, indicating the recruitment of CD8+ T cells post-MTB infection (Munk and Emoto, 1995; Tully et al, 2005)
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