In Brief

Inflammation

Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity Brydges, S. D. et al. Immunity 4 Jun 2009 (doi:10.1016/j.immuni.2009.05.005)

A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses Meng, G. et al. Immunity 4 Jun 2009 (doi:10.1016/j.immuni.2009.04.012)

Missense mutations in the inflammasome component NLR family, pyrin domain-containing 3 (NLRP3; also known as NALP3) leading to excessive production of interleukin-1β (IL-1β) have been associated with several cryopyrin-associated periodic syndromes (CAPS). Through the generation of gene-targeted mice that express NLRP3 containing various mutations that are similar to those identified in patients with CAPS, these two studies provide insights into the pathogenesis of inflammasome-mediated diseases.

The three mutant mouse strains (two generated by Brydges et al. and one by Meng et al.) showed varied phenotypes and mortality rates, but all mice developed severe autoinflammation. Both studies showed that activation of Nlrp3-mutant but not wild-type antigen-presenting cells (APCs) by low amounts of lipopolysaccharide in the absence of exogenous ATP resulted in high levels of IL-1β secretion, suggesting a lower inflammasome activation threshold. In addition, the autoinflammatory phenotypes were dependent on inflammasome hyperactivation specifically in APCs, and increased IL-1β production had a central, but not exclusive, role in the disease phenotype.

Meng et al. showed that APCs from mutant mice enhanced T helper 17 (T_H17) cell differentiation but inhibited the differentiation of other T_H cell subsets under polarizing conditions. Moreover, skin inflammation in the mutant mice could be reduced by blocking either IL-1 receptor signalling or IL-17A. By contrast, Brydges et al. showed that although APCs from their mutant mice could enhance T_H1 and T_H17 cell differentiation under polarizing conditions, a similar disease phenotype was observed if the mutant mice also lacked T cells, suggesting that T cells do not have a central role in CAPS-associated autoinflammation.

Antigen presentation

IRAP identifies an endosomal compartment required for MHC class I cross-presentation Saveanu, L. et al. Science 4 Jun 2009 (doi:10.1126/science.1172845)

This study identified insulin-regulated aminopeptidase (IRAP) as being involved in the trimming of exogenous peptides for cross-presentation on MHC class I molecules. IRAP was strongly enriched in early phagosomes that express RAB14 — a protein that prevents phagosome fusion with acidic lysosomes, which could be detrimental for cross-presentation — where it colocalized with MHC class I molecules. IRAP-deficient mice presented endogenous MHC class I-restricted antigens normally in a manner dependent on endoplasmic reticulum aminopeptidases (ERAPs), but the cross-presentation of exogenous antigens was inhibited by the absence of both ERAPs and the endosomal peptidase IRAP in an additive manner; ERAP and IRAP are functionally redundant but do not colocalize in the same intracellular compartment. This indicates that there are two parallel pathways for cross-presentation that involve loading of MHC class I molecules in the ER and endosomes.