ESAT6 differentially inhibits IFN‐γ‐inducible class II transactivator isoforms in both a TLR2‐dependent and ‐independent manner

Abstract

Mycobacterium tuberculosis (Mtb) downregulates the surface expression of major histocompatibility class II (MHC II) molecules on macrophages via modulating class II transactivator (CIITA) protein of the host cell. This results in decreased effector function of CD4(+) T cells. In macrophages, CIITA is transcribed by the promoters I (pI) and IV (pIV) and the corresponding gene products are referred to as type I and type IV CIITA, respectively. Earlier studies have mainly focused on CIITA transcribed by pIV; however, these studies also showed that type IV CIITA expression was transient and dispensable for MHC II expression. In the present study, we observed that the Mtb 6-kDa, early secreted antigen (ESAT6) inhibited interferon (IFN)-γ-induced type I as well as type IV CIITA, but, interestingly, inhibition of type I CIITA was found to be independent of Toll-like receptor-2 (TLR2), whereas that of type IV was TLR2 dependent. Moreover, we also present evidence to show that ESAT6-mediated inhibition was regulated via remodeling of the chromatin. We found that ESAT6 caused a decrease in the IFN-γ-stimulated methylation of the histone H3K4, as well as in the levels of histone acetylation at the CIITA pI locus in macrophages. We also found the involvement of mitogen-activated protein kinases ERK1/2 and p38 in the regulation of CIITA by ESAT6. In conclusion, our studies suggest that ESAT6 could inhibit the expression of type I and type IV CIITA through different pathways. Furthermore, ESAT6 could signal through putative receptors other than TLR2, and that the inhibition of IFN-γ-stimulated CIITA by ESAT6 was regulated at the chromatin level.

Early secretory antigenic target-6 of Mycobacterium tuberculosis: enigmatic factor in pathogen–host interactions

“…In the case of M. tb infection, the main PRRs that contribute to pathogen recognition and subsequent cellular signalling are toll like receptor (TLR) 2 and TLR9 [42]. M. tb also interferes with the expression of MHC class II molecules through ESAT6 [43]. It has been shown that ESAT6 interacts with TLR2 and modulates host immune responses [44].…”

Immune regulatory activities of early secreted antigenic target of 6-kD protein of Mycobacterium tuberculosis and implications for tuberculosis vaccine design

“…29 The same group has demonstrated that ESAT-6 decreases IFN-γ induced expression of MHC class II expression by inhibiting MHC class II transactivator expression through regulating chromatin remodeling. 30 These changes reduce the efficiency of antigen presentation by macrophages, therefore may affect effective induction of T cell immune responses against tuberculosis infection. Studies led by Dr. Basu demonstrated that ESAT-6 decreases LPS-stimulated IL-12 p40 production by mouse macrophages through inhibiting TLR4-mediated MAPK activation and NF-κB activation.…”

Mycobacterium tuberculosis RD-1 Secreted Antigens as Protective and Risk Factors for Tuberculosis

“…This binding caused inactivation of transcription factors interferon regulatory factors (IRF) and NF-ĸB. Recent observations from our lab have shown that ESAT-6 down-regulates IFN- inducible expression of type I and type IV isomers of MHC class II transactivator (CIITA) in macrophages (Kumar et al, 2011). Interestingly, the downregulation of type I CIITA was independent of TLR-2 while the effect on type IV CIITA was mediated through TLR-2.…”