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International Immunology, Vol. 15, No. 10, pp. 1249-1263, October 2003
© 2003 Japanese Society for Immunology

The MHC class II ß chain cytoplasmic tail overcomes the invariant chain p35-encoded endoplasmic reticulum retention signal

Hayssam Khalil1, Alexandre Brunet1, Ingrid Saba1, Rafik Terra1, Rafick Pierre Sékaly2,4 and Jacques Thibodeau1

1 Laboratoire d’Immunologie Moléculaire and 2 Laboratoire d’Immunologie, Département de Microbiologie et Immunologie, Faculté de Médecine, Université de Montréal, CP 6128 Succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada 3 Department of Experimental Medicine, McGill School of Medicine, Montréal H3G 1A4, Canada 4 Laboratoire d’Immunologie, Hôpital Hôtel-Dieu, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal H2W 1T8, Canada

Correspondence to: J. Thibodeau; E-mail: Jacques.Thibodeau{at}umontreal.ca
Transmitting editor: C. J. Paige

The human-specific p35 isoform of the invariant chain (Ii) includes an R-X-R endoplasmic reticulum (ER) retention motif that is inactivated upon HLA-DR binding. Although the masking is assumed to involve the cytoplasmic tails of class II molecules, the mechanism underlying this function remains to be investigated. Moreover, in light of the polymorphic nature of the class II cytosolic tails, little is known about the capacity of various isotypes or alleles to overcome the retention signal of Iip35. To gain further insights into these issues, we first addressed the proposed role of the HLA-DR cytoplasmic tails. As shown by flow cytometry, the presence of Iip35 in transfected HeLa cells prevented surface expression of HLA-DR molecules lacking their cytoplasmic tails (DR{alpha}TM/ßTM). These truncated class II molecules and Iip35 accumulated in the ER, and co-localized with calnexin, as determined by confocal microscopy. Sensitivity of DR{alpha}TM/ßTM to endoglycosidase H treatment confirmed that these molecules do not reach the trans-Golgi network when associated with Iip35. Further characterization revealed that the ß chain cytosolic tail is critical for efficient ER egress of class II/Iip35 complexes. Interestingly, our results clearly demonstrate for the first time that DP and DQ isotypes can also overcome the retention motif of Iip35 through a mechanism involving their very distinctive polymorphic ß chain cytoplasmic tails. Altogether, these results further dissect the masking of di-basic retention signals, and emphasize the interplay between class II molecules and Ii for the transport of the complex to the endocytic pathway.

Keywords: antigen presentation, di-arginine, HLA, Iip35, R-X-R


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