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Major Histocompatibility Complex (MHC) Class I Kbdb / Deficient Mice Proc. Natl. Acad. Sci. USA Vol. 95, pp. 12492–12497, October 1998 Immunology Major histocompatibility complex (MHC) class I KbDb 2y2 deficient mice possess functional CD81 T cells and natural killer cells YULIA VUGMEYSTER*, RICKARD GLAS*, BE´ATRICE PE´RARNAU†,FRANC¸OIS A. LEMONNIER†,HERMAN EISEN‡, AND HIDDE PLOEGH*§ *Department of Pathology, Harvard Medical School, Boston, MA 02115; †Unite´d’Immunite´Cellulaire Antivirale, Institut Pasteur, Paris, France; and ‡Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142 Contributed by Herman N. Eisen, August 25, 1998 2y2 b 2y2 ABSTRACT We obtained mice deficient for major histo- expressed on the cell surface of TAP and 2m animals, compatibility complex (MHC) molecules encoded by the H-2K so that total MHC I cell-surface levels are decreased at most and H-2D genes. H-2 KbDb 2y2 mice express no detectable 10-fold (12, 13). Although such empty class I molecules decay classical MHC class I-region associated (Ia) heavy chains, al- rather rapidly in ex vivo cultured cells, nothing is known about b 2y2 b 2y2 though 2-microglobulin and the nonclassical class Ib proteins their half-life in vivo.TAP and 2m animals also examined are expressed normally. KbDb 2y2 mice have greatly possess a limited repertoire of self-MHC class I-restricted CD81 reduced numbers of mature CD81 T cells, indicating that T cells, which can be explained by their selection on the remaining selection of the vast majority (>90%) of CD81 T cells cannot be low levels of MHC class I (14–17). These animals reject allogeneic b compensated for by 2-microglobulin-associated molecules other skin grafts and tumors and give rise to viral and allogeneic CD81 than classical H-2K and D locus products. In accord with the T cell-mediated responses (14, 17–21), consistent with the con- greatly reduced number of CD81 T cells, spleen cells from KbDb tinued presence of functional MHC class I proteins. 2y2 mice do not generate cytotoxic responses in primary In addition to the classical H-2K and H-2D MHC class I loci, mixed-lymphocyte cultures against MHC-disparate (allogeneic) there are fewer polymorphic MHC class I-encoded proteins cells. However, in vivo priming of KbDb 2y2 mice with allogeneic (encoded by genes in the Q, T and M regions; refs. 22 and 23). cells resulted in strong CD81 MHC class Ia-specific allogeneic Moreover, there are additional genes, clearly related more closely responses. Thus, a minor population of functionally competent to MHC class I genes than to any other gene family, but not linked peripheral CD81 T cells capable of strong cytotoxic activity to the MHC (CD1, ZAG, FcRn, and HFE; refs. 22–27). Both arises in the complete absence of classical MHC class Ia mole- MHC-linked and MHC-unlinked class I genes of this type are cules. KbDb 2y2 animals also have natural killer cells that called MHC class Ib genes, and the molecules they encode (MHC retain their cytotoxic potential. class Ib proteins) are structurally similar to the classical MHC b class Ia proteins. Many of the class Ib molecules require 2m and Major histocompatibility complex (MHC) class I molecules, possibly TAP-dependent peptides for their folding and transport expressed on almost all nucleated cells of the body, are to the cell surface (28). In some cases, presentation of peptides by heterodimeric type I membrane proteins, composed of an class Ib proteins to ab or gd T cells has been shown (28). b b MHC-encoded class I heavy chain, a 2-microglobulin ( 2m) Nonclassical MHC molecules are functionally diverse. For light chain, and a short peptide 8–10 aa in length, all of which example, the FcRn receptor transports IgG from ingested milk are essential for the formation of a stable MHC class I protein across the intestinal epithelium of neonatal mice and rescues (1). Those MHC class I proteins whose heavy chains are circulating IgG from degradation (24). In addition, CD1 plays a encoded by highly polymorphic genes (H-2K, D, and L in mice) crucial role in the function of NK1.1 T cells and in their positive are termed ‘‘classical’’ or class I-region associated (Ia) MHC. selection (26, 29). H-2 M3a presents N-formylated peptides Cell-surface MHC class Ia proteins are essential for the thymic derived from certain bacterial and mitochondria-encoded pro- development of CD81 T cells (2) and for providing protection teins, whereas MHC class Ia molecules do not seem to bind such against lysis by natural killer (NK) cells (3). Recent work peptides (25, 30, 31). Expression of H-2 Qa-2 has been correlated suggests that cell-surface MHC class Ia proteins are also with the expression of an early embryo gene, Ped, that maps in the involved critically in maintaining the levels of memory CD81 H-2 Qa-2 region and controls the rate of preimplantation em- T cells in the periphery (4, 5). For studies of these processes, bryonic development (32). Though the functional role of Qa-2 in mice that are totally deficient in the classical class I MHC the immune response is not known, it binds a wide variety of proteins would be valuable. peptides, and its expression depends on TAP (32). Because of the b b Mice deficient for 2m or the MHC-encoded peptide trans- requirement of 2m and TAP in the expression of nonclassical porter (TAP), a complex involved in loading peptides onto newly MHC molecules (22, 33), many class Ib molecules fail to be b synthesized MHC class I proteins, do not express normal levels of expressed on cells in animals that lack 2m or TAP. Combined, b 2y2 2y2 cell-surface MHC class I proteins and consequently are defective these findings suggest that neither 2m nor TAP mice in MHC class I-restricted antigen presentation and in thymic can be considered ideal models for mice whose lack of MHC class 1 2y2 b 2y2 selection of CD8 T cells (6–8). These TAP and 2m Ia molecules is complete and limited to only the classical MHC mice have been used widely as MHC class I-deficient models, but class Ia molecules. this deficiency is not complete. Thus, a sizable fraction of MHC Besides their well established role as restriction elements for class I heavy chains apparently folds normally and is transported T cell recognition, MHC class I molecules are also involved in b to the cell surface even in the absence of 2m (in particular, the H-2Db gene product) or in the absence of TAP-dependent Abbreviations: b2m, b2-microglobulin; CTL, cytotoxic T lymphocyte; peptides (8–12). In addition, ‘‘empty’’ class I molecules are FACS, fluorescence-activated cell sorter; FITC, fluorescein isothio- cyanate; Ia, I-region associated; MHC, major histocompatibility com- The publication costs of this article were defrayed in part by page charge plex; MLC, mixed-lymphocyte culture; NK, natural killer; PE, phyco- erythrin; RAFHC, rabbit anti-MHC I free heavy chain; TAP, peptide payment. This article must therefore be hereby marked ‘‘advertisement’’ in transporter; TCR, T cell receptor. accordance with 18 U.S.C. §1734 solely to indicate this fact. §To whom reprint requests should be addressed at: Department of © 1998 by The National Academy of Sciences 0027-8424y98y9512492-6$2.00y0 Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, PNAS is available online at www.pnas.org. MA 02115. e-mail: [email protected]. 12492 Downloaded by guest on September 29, 2021 Immunology: Vugmeyster et al. Proc. Natl. Acad. Sci. USA 95 (1998) 12493 providing protection from lysis by NK cells (3, 34–36). Little Peptide N-Glycosidase Treatment and Immunoblotting. Tis- is known about the development of NK cells, but a number of sues from different organs were homogenized in 0.5–2 ml of reports support the existence of an educational process for Nonidet P-40 lysis mix and incubated at 4°C for 1 h. Lysates were NK-cell tolerance, and it has been proposed that NK cells spun for 30 min at 14,000 rpm in an Eppendorf centrifuge and calibrate to endogenous levels of self-MHC class I during diluted in lysis mix to 2 mgyml total protein. Lysates were then b 2y2 development. For example, 2m mice possess functional heat-denatured in 0.6 M 2-mercaptoethanol and 2.4% SDS at b 2y2 but self-tolerant NK cells, whereas 2m Con A-stimu- 95°C and treated for4hat30°C with peptide N-glycosidase in b lated blasts are killed by NK cells from 2m-expressing pa- PBS containing 25 mM EDTA, 1% Nonidet P-40, 0.4% SDS, and rental mice (37, 38). The mechanism of this self-tolerance is 0.1 M 2-mercaptoethanol. Lysates were then separated by SDSy not well understood but includes the regulation of NK-cell PAGE and transferred to nitrocellulose. The filters were incu- inhibitory receptors. In addition, recent reports show that bated with the indicated first antibodies (RAFHC 1:1000 and NK-cell reactivity may also depend on MHC class Ib molecules anti-exon 8 of Kb antibodies 1:2000), followed by horseradish- b 2y2 (39, 40), which are not expressed normally in either 2m peroxidase-coupled goat anti-mouse or anti-rabbit IgG. The or TAP 2y2 mice. This further motivates the use of mice that immune complexes were visualized by chemiluminescence. are selectively deficient for MHC class Ia in such studies. Flow-Cytometry Evaluation of MHC I, CD4, CD8, and TCR To obtain MHC class Ia deficient animals, we took advantage Surface Expression. Screening for KbDb 2y2 mice was done of mice of the 129 strain with defective K or D genes, which by collecting '100 ml of tail blood into 50 mM EDTA in PBS.
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