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The murine nonclassical class I major histocompatibility complex-like CD1.1 molecule protects target cells from lymphokine-activated killer cell cytolysis.

Chang CS, Brossay L, Kronenberg M, Kane KP - J. Exp. Med. (1999)

Bottom Line: Passage of effector cells in recombinant interleukin (rIL)-2 enhanced protection by mCD1.1, suggesting an expansion of relevant A-LAK population(s) or modulation of A-LAK receptor expression.CD1.1 is by far the most divergent class I molecule capable of regulating NK cell activity.Finally, mCD1.1 expression rendered RMA/S cells resistant to lysis by A-LAK of multiple mouse strains.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology and Immunology, Faculty of Medicine, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.

ABSTRACT
Classical class I major histocompatibility complex (MHC) molecules, as well as the nonclassical class I histocompatibility leukocyte antigen (HLA)-E molecule, can negatively regulate natural killer (NK) cell cytotoxicity through engagement of NK inhibitory receptors. We show that expression of murine (m)CD1.1, a nonpolymorphic nonclassical MHC class I-like molecule encoded outside the MHC, protects NK-sensitive RMA/S target cells from adherent lymphokine-activated killer cell (A-LAK) cytotoxicity. Passage of effector cells in recombinant interleukin (rIL)-2 enhanced protection by mCD1.1, suggesting an expansion of relevant A-LAK population(s) or modulation of A-LAK receptor expression. Murine CD1. 1 conferred protection from lysis by rIL-2-activated spleen cells of recombination activating gene (Rag)-1(-/-) mice, which lack B and T cells, demonstrating that mCD1.1 can protect RMA/S cells from lysis by NK cells. An antibody specific for mCD1.1 partially restored A-LAK lysis of RMA/S.CD1.1 transfectants, indicating that cell surface mCD1.1 can confer protection from lysis; therefore, mCD1.1 possibly acts through interaction with an NK inhibitory receptor. CD1.1 is by far the most divergent class I molecule capable of regulating NK cell activity. Finally, mCD1.1 expression rendered RMA/S cells resistant to lysis by A-LAK of multiple mouse strains. The conserved structure of mCD1.1 and pattern of mCD1.1 resistance from A-LAK lysis suggest that mCD1.1 may be a ligand for a conserved NK inhibitory receptor.

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Cytotoxicity by A-LAKs generated from NZB/BinJ (A) and  CBA/J mice (B) is inhibited by mCD1.1. The day 3, 5, and 7 A-LAKs  from both strains of mice were incubated with 51Cr-labeled RMA/S (⋄)  or RMA/S.CD1.1 (○) target cells. Each data point is the mean of triplicate wells ± SD. Spontaneous release values were <15%. This experiment was performed twice with effector cells from both mouse strains.
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Figure 6: Cytotoxicity by A-LAKs generated from NZB/BinJ (A) and CBA/J mice (B) is inhibited by mCD1.1. The day 3, 5, and 7 A-LAKs from both strains of mice were incubated with 51Cr-labeled RMA/S (⋄) or RMA/S.CD1.1 (○) target cells. Each data point is the mean of triplicate wells ± SD. Spontaneous release values were <15%. This experiment was performed twice with effector cells from both mouse strains.

Mentions: Since CD1 is a nonpolymorphic class I MHC molecule, this implies that any NK receptor(s) which may mediate negative regulatory signal(s) upon mCD1.1 engagement could be conserved in mice. Thus, mCD1.1 may be able to inhibit the cytotoxic activities of A-LAKs derived from different inbred mouse strains. To test this hypothesis, we generated A-LAKs from two additional mouse strains, CBA/J (H-2k) and NZB/ BinJ (H-2d). The results indicated that the A-LAKs from these mouse strains exhibit similar patterns of mCD1.1-mediated inhibition as seen in the B6 A-LAKs (Fig. 6, A and B). For instance, the day 3 A-LAKs lysed RMA/S and RMA/S.CD1.1, whereas a significant reduction in lysis of RMA/S.CD1.1 relative to RMA/S was detected if day 5 and 7 A-LAKs were used as effectors. It is perhaps worth noting that the patterns of inhibition among these mice are not exactly identical. In both B6 and NZB/BinJ mice, RMA/S is highly susceptible to lysis by all A-LAK populations, and the reduction of RMA/S.CD1.1 lysis becomes clear in those A-LAKs obtained at later time points (Fig. 2, and Fig. 6 A). In contrast, A-LAKs derived from CBA/J show a somewhat different kinetic pattern. The day 3 A-LAKs have low cytotoxicity against RMA/S, and it only became strongly observable with day 7 A-LAKs (Fig. 6 B), whereas RMA/S.CD1.1 remained relatively resistant to A-LAKs obtained at all of the various culture periods with rIL-2 (Fig. 6 B). The reasons for the somewhat different kinetic inhibition patterns are not clear. Nevertheless, these results demonstrate that mCD1.1 is able to suppress A-LAK activities of different mouse strains expressing distinct H-2 haplotypes, consistent with the possibility that a conserved NK inhibitory receptor(s) for mCD1.1 may exist that is able to suppress A-LAK cytotoxic activity.


The murine nonclassical class I major histocompatibility complex-like CD1.1 molecule protects target cells from lymphokine-activated killer cell cytolysis.

Chang CS, Brossay L, Kronenberg M, Kane KP - J. Exp. Med. (1999)

Cytotoxicity by A-LAKs generated from NZB/BinJ (A) and  CBA/J mice (B) is inhibited by mCD1.1. The day 3, 5, and 7 A-LAKs  from both strains of mice were incubated with 51Cr-labeled RMA/S (⋄)  or RMA/S.CD1.1 (○) target cells. Each data point is the mean of triplicate wells ± SD. Spontaneous release values were <15%. This experiment was performed twice with effector cells from both mouse strains.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2192909&req=5

Figure 6: Cytotoxicity by A-LAKs generated from NZB/BinJ (A) and CBA/J mice (B) is inhibited by mCD1.1. The day 3, 5, and 7 A-LAKs from both strains of mice were incubated with 51Cr-labeled RMA/S (⋄) or RMA/S.CD1.1 (○) target cells. Each data point is the mean of triplicate wells ± SD. Spontaneous release values were <15%. This experiment was performed twice with effector cells from both mouse strains.
Mentions: Since CD1 is a nonpolymorphic class I MHC molecule, this implies that any NK receptor(s) which may mediate negative regulatory signal(s) upon mCD1.1 engagement could be conserved in mice. Thus, mCD1.1 may be able to inhibit the cytotoxic activities of A-LAKs derived from different inbred mouse strains. To test this hypothesis, we generated A-LAKs from two additional mouse strains, CBA/J (H-2k) and NZB/ BinJ (H-2d). The results indicated that the A-LAKs from these mouse strains exhibit similar patterns of mCD1.1-mediated inhibition as seen in the B6 A-LAKs (Fig. 6, A and B). For instance, the day 3 A-LAKs lysed RMA/S and RMA/S.CD1.1, whereas a significant reduction in lysis of RMA/S.CD1.1 relative to RMA/S was detected if day 5 and 7 A-LAKs were used as effectors. It is perhaps worth noting that the patterns of inhibition among these mice are not exactly identical. In both B6 and NZB/BinJ mice, RMA/S is highly susceptible to lysis by all A-LAK populations, and the reduction of RMA/S.CD1.1 lysis becomes clear in those A-LAKs obtained at later time points (Fig. 2, and Fig. 6 A). In contrast, A-LAKs derived from CBA/J show a somewhat different kinetic pattern. The day 3 A-LAKs have low cytotoxicity against RMA/S, and it only became strongly observable with day 7 A-LAKs (Fig. 6 B), whereas RMA/S.CD1.1 remained relatively resistant to A-LAKs obtained at all of the various culture periods with rIL-2 (Fig. 6 B). The reasons for the somewhat different kinetic inhibition patterns are not clear. Nevertheless, these results demonstrate that mCD1.1 is able to suppress A-LAK activities of different mouse strains expressing distinct H-2 haplotypes, consistent with the possibility that a conserved NK inhibitory receptor(s) for mCD1.1 may exist that is able to suppress A-LAK cytotoxic activity.

Bottom Line: Passage of effector cells in recombinant interleukin (rIL)-2 enhanced protection by mCD1.1, suggesting an expansion of relevant A-LAK population(s) or modulation of A-LAK receptor expression.CD1.1 is by far the most divergent class I molecule capable of regulating NK cell activity.Finally, mCD1.1 expression rendered RMA/S cells resistant to lysis by A-LAK of multiple mouse strains.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology and Immunology, Faculty of Medicine, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.

ABSTRACT
Classical class I major histocompatibility complex (MHC) molecules, as well as the nonclassical class I histocompatibility leukocyte antigen (HLA)-E molecule, can negatively regulate natural killer (NK) cell cytotoxicity through engagement of NK inhibitory receptors. We show that expression of murine (m)CD1.1, a nonpolymorphic nonclassical MHC class I-like molecule encoded outside the MHC, protects NK-sensitive RMA/S target cells from adherent lymphokine-activated killer cell (A-LAK) cytotoxicity. Passage of effector cells in recombinant interleukin (rIL)-2 enhanced protection by mCD1.1, suggesting an expansion of relevant A-LAK population(s) or modulation of A-LAK receptor expression. Murine CD1. 1 conferred protection from lysis by rIL-2-activated spleen cells of recombination activating gene (Rag)-1(-/-) mice, which lack B and T cells, demonstrating that mCD1.1 can protect RMA/S cells from lysis by NK cells. An antibody specific for mCD1.1 partially restored A-LAK lysis of RMA/S.CD1.1 transfectants, indicating that cell surface mCD1.1 can confer protection from lysis; therefore, mCD1.1 possibly acts through interaction with an NK inhibitory receptor. CD1.1 is by far the most divergent class I molecule capable of regulating NK cell activity. Finally, mCD1.1 expression rendered RMA/S cells resistant to lysis by A-LAK of multiple mouse strains. The conserved structure of mCD1.1 and pattern of mCD1.1 resistance from A-LAK lysis suggest that mCD1.1 may be a ligand for a conserved NK inhibitory receptor.

Show MeSH
Related in: MedlinePlus