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ESAT6 differentially inhibits IFN‐γ‐inducible class II transactivator isoforms in both a TLR2‐dependent and ‐independent manner
Author(s) -
Kumar Pavanish,
Agarwal Richa,
Siddiqui Imran,
Vora Hardeep,
Das Gobardhan,
Sharma Pawan
Publication year - 2012
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/icb.2011.54
Subject(s) - ciita , biology , mhc class ii , microbiology and biotechnology , histone h3 , stat1 , tlr2 , signal transduction , histone , major histocompatibility complex , antigen , immunology , gene , genetics , tlr4
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.