Alternate class I MHC antigen processing is inhibited by Toll-like receptor signaling pathogen-associated molecular...

Area of Science:

• Immunology
• Microbiology
• Cellular Biology

Background:

• Pathogen-associated molecular patterns (PAMPs) activate immune responses via Toll-like receptors (TLRs).
• Prolonged PAMP exposure, particularly from Mycobacterium tuberculosis (MTB), can inhibit major histocompatibility complex class II (MHC-II) expression and antigen processing, potentially aiding immune evasion.
• The impact of PAMPs on the alternate MHC class I (MHC-I) antigen processing pathway remains largely unknown.

Purpose of the Study:

• To investigate the effect of PAMPs, including those from MTB, on the alternate MHC-I antigen processing pathway in macrophages.
• To determine the role of specific Toll-like receptors (TLRs) and myeloid differentiation factor 88 (MyD88) in PAMP-mediated inhibition of antigen processing pathways.

Main Methods:

• Macrophages were activated with interferon-gamma (IFN-γ) and exposed to various PAMPs (MTB, MTB 19-kDa lipoprotein, CpG DNA, LPS).
• Alternate MHC-I processing of latex-conjugated antigens was assessed.
• MHC-II expression, phagosome maturation, and antigen degradation were analyzed.
• The role of TLR-2 and MyD88 was investigated using genetic knockouts or specific inhibitors.

Main Results:

• MTB and TLR-signaling PAMPs inhibited alternate MHC-I antigen processing in IFN-γ-activated macrophages.
• Inhibition was dependent on MyD88 for MTB and all tested PAMPs.
• TLR-2 was specifically required for inhibition by MTB 19-kDa lipoprotein.
• Inhibition of both MHC-II and alternate MHC-I processing occurred after 16 hours of PAMP exposure, mimicking chronic infection.
• Phagosome maturation and antigen degradation were inhibited by MTB 19-kDa lipoprotein and other PAMPs in a MyD88-dependent manner.
• MHC-I expression and conventional MHC-I antigen processing were not inhibited.

Conclusions:

• Prolonged exposure to MTB and other PAMPs inhibits both MHC-II and alternate MHC-I antigen processing pathways in macrophages.
• This dual inhibition, occurring after 16 hours, may represent a mechanism for pathogens to evade immune surveillance by both CD4(+) and CD8(+) T cells.
• Inhibition of phagosome maturation and degradation contributes to reduced antigen availability for MHC-I presentation.
• These findings suggest a strategy employed by persistent intracellular pathogens like MTB to establish chronic infections by silencing macrophage antigen presentation.