NKT Cell Activation During (Microbial) Infection
Invariant Natural Killer T (iNKT) cells constitute an innate-like lymphocyte population endowed with powerful immunomodulatory functions. Unlike conventional T cells, iNKT cells predominantly express a conserved semi-invariant T cell receptor (TCR), Vα14-Jα18/Vβ2, 7, 8 in mice and Vα24-Jα18/Vβ11 in humans. These canonical TCRs in both species do not recognize peptides, but glycosphingolipid (GSL) patterns presented by CD1d on antigen presenting cells (APCs). The natural mechanisms for iNKT cell activation were unclear prior to the recent identification of their endogenous and exogenous GSL ligands.
Microbes can employ two alternative strategies for iNKT cell activation as exemplarily shown here for Gram-negative bacteria: (a) recognition of endogenous GSLs – by-products of the complex mammalian GSL metabolic pathways – and the presence of interleukin-12 (IL-12), triggered by Toll-like receptor (TLR) signaling of infected APCs, are required for the early secretion of IFN- g by iNKT cells in response to Gram-negative, LPS-positive bacteria. Whereas iNKT cells are secondary to APC-mediated effects in infections with these bacteria, (b) iNKT cells accelerate the clearance of Gram-negative LPS-negative alphaproteobacteria due to the cognate recognition of GSLs in the cell wall of these alphaproteobacteria. Thus, the iNKT cell population represents a major innate recognition pathway for these LPS-negative, GSL-positive alphaproteobacteria that senses infection at sites where iNKT cells accumulate, such as the liver. In this context, iNKT cell activation upon microbial encounter may not only contribute to bacterial clearance, but may be even deleterious for the host, providing innate signals that break peripheral tolerance and unleash autoimmune effector cells.
KeywordsMajor Histocompatibility Complex Major Histocompatibility Complex Class Primary Biliary Cirrhosis iNKT Cell Primary Biliary Cirrhosis Patient
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