Cutting Edge: Viral Infection Breaks NK Cell Tolerance to ''Missing Self'' Joseph C

Cutting Edge: Viral Infection Breaks NK Cell Tolerance to ''Missing Self'' Joseph C. Sun and Lewis L. Lanier This information is current as J Immunol 2008; 181:7453-7457; ; of September 24, 2021. doi: 10.4049/jimmunol.181.11.7453 http://www.jimmunol.org/content/181/11/7453 Downloaded from References This article cites 25 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/181/11/7453.full#ref-list-1

Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision

• No Triage! Every submission reviewed by practicing scientists

• Fast Publication! 4 weeks from acceptance to publication

*average by guest on September 24, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts

The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Cutting Edge

Cutting Edge: Viral Infection Breaks NK Cell Tolerance to “Missing Self”1 Joseph C. Sun and Lewis L. Lanier2

NK cells attack cells lacking MHC class I, yet MHC Recent studies have suggested that NK cells undergo “licens- class I-deficient mice have normal numbers of NK cells ing” or “disarming” in the bone marrow, a process that dictates with intact, albeit diminished, functions. Moreover, the proper development of NK cells (8, 9). Immature NK cells wild-type NK cells are tolerant of MHC class I-deficient expressing inhibitory receptors that can interact with their au- cells in mixed bone marrow chimeras. In this study, we tologous MHC class I molecules go on to functional maturity. investigated how the absence of MHC class I affects In the absence of these interactions, NK cells either fail to com-

plete their maturation or are chronically stimulated, with either Downloaded from NK cells. NK cells from ␤ -microglobulin-deficient ؊ ؊ 2 scenario resulting in hyporesponsive NK cells in the periphery (B2m / ) and wild-type mice exhibit similar pheno- ؊ ؊ (8, 9). Thus, these models predict that in mice lacking MHC typic and functional characteristics. Both B2m / and ؉ class I, selective pressures ensure self-tolerance in developing wild-type Ly49H NK cells proliferated robustly and NK cells that are unable to engage their inhibitory receptors. produced IFN-␥ after infection with mouse CMV. Challenging the “licensing” and “disarming” models of NK ؊/؊

NK cells in mixed wild-type:B2m chimeric mice cell unresponsiveness are studies showing robust NK cell acti- http://www.jimmunol.org/ Ϫ Ϫ were initially tolerant of MHC class I-deficient host vation and effector function in B2m / mice following viral, cells. However, this tolerance was gradually lost over bacterial, and parasite infections (8, 10–12). In this study, we time and after mouse CMV infection was rapidly bro- addressed these issues by examining the phenotype and func- Ϫ Ϫ Ϫ Ϫ ken, with a pronounced rejection of host B2m / he- tion of NK cells from B2m / mice, either in noninfected or virus-infected animals. Furthermore, we generated mixed wild- matopoietic cells. Thus, although NK cells can be Ϫ Ϫ type:B2m / bone marrow chimeric mice to study the toler- held in check against “missing self,” acute inflamma- Ϫ/Ϫ tion driven by infection can rapidly break established ance of wild-type NK cells to B2m host cells that are “miss- self-tolerance. The Journal of Immunology, 2008, ing self” in an environment where these NK cells were resting or by guest on September 24, 2021 activated by viral infection. 181: 7453–7457. Materials and Methods arre’s “missing self” hypothesis posits that NK cells Mice and infections can recognize or “sense” the loss of MHC class I (or C57BL/6 (B6) and congenic (CD45.1) mice were purchased from the National Ϫ/Ϫ “self”) on potential target cells and become activated Cancer Institute (Bethesda, MD). B2m B6 mice were bred at University of K California (UCSF), San Francisco, CA. Experiments were done according to (1). Over two decades of research has supported this hypothesis, the UCSF Institutional Animal Care and Use Committee guidelines. Mice were with several studies convincingly showing that NK cells in wild- infected by i.p. injections of MCMV (Smith strain, 5 ϫ 104 PFU). NK cells ␮ type mice are solely responsible for the rejection of MHC class were depleted by injection with 200 g of anti-NK1.1 mAb PK136. I-deficient cells (2–4). Interestingly, MHC class I-deficient Generation of mixed bone marrow chimeric mice ␤ Ϫ/Ϫ 3 animals (such as 2-microglobulin-deficient (B2m ), Mixed bone marrow chimeric mice were generated as described previously Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ TAP1 / ,orH2-D / K / mice) contain relatively normal (13). Briefly, NK cells were depleted from B6 (CD45.1 ϫ CD45.2) mice by ␮ numbers of NK cells (4–7) and yet do not succumb to autoim- injection with 200 g of anti-NK1.1 mAb, and then mice were irradiated with 1000 rad from a 137Cs source. One day later, mice were injected i.v. munity. If NK cell-mediated rejection of MHC class I-deficient with a 1:1 or 10:1 mixture of bone marrow cells isolated from wild-type cells is indeed robust, why is it that NK cells in the periphery of congenic (CD45.1ϩ) and B2mϪ/ Ϫ(CD45.2ϩ) mice. Donor mice were also Ϫ Ϫ B2m / mice do not target self-tissues for destruction? What pretreated by injection with 200 ␮g of anti-NK1.1 mAb 24 h before harvest Ϫ/Ϫ of bone marrow to eliminate donor NK cells from the bone marrow graft. are the regulatory mechanisms that keep NK cells in B2m Peripheral blood leukocytes from chimeric mice were analyzed at various mice in check? time points after bone marrow reconstitution to assess the ratio of wild-type

Department of Microbiology and Immunology and the Cancer Research Institute, Uni- 2 Address correspondence and reprint requests to Dr. Lewis Lanier, Department of Micro- versity of California, San Francisco, CA 94143 biology and Immunology, University of California 513 Parnassus Avenue, Box 0414, Health Sciences East 1001G, San Francisco, CA 94143. E-mail address: Lewis.Lanier@ Received for publication September 3, 2008. Accepted for publication October 2, 2008. ucsf.edu The costs of publication of this article were defrayed in part by the payment of page charges. Ϫ Ϫ 3 Abbreviations used in this paper: B2m / , ␤ -microglobulin deficient; B6, C57BL/6; This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. 2 KLRG1, killer cell lectin-like receptor G1; MCMV, mouse CMV. Section 1734 solely to indicate this fact. 1 National Institutes of Health Grant AI068129 supported this work. J.C.S. is supported Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 by the Irvington Institute for Immunological Research. L.L.L. is an American Cancer So- ciety Research Professor.

www.jimmunol.org 7454 CUTTING EDGE: BREAKING TOLERANCE TO MISSING SELF and B2mϪ/Ϫ cells, and the animals were infected at ϳ10 wk following bone marrow reconstitution. Ex vivo stimulation of NK cells 1,2-Dioleoyloxy-3-(trimethylammonium)propane (DOTAP)-treated tissue culture plates were coated with Abs specific for Ly49H (provided by Dr. W. Yokoyama, Washington University School of Medicine, St. Louis, MO) (or uncoated wells as negative control) and whole splenocytes were incubated for 5 h at 37°C in the presence of brefeldin A (BD Pharmingen), followed by staining for intracellular cytokines (14). Flow cytometry Single-cell suspensions of spleen and liver were prepared. Fc receptors were blocked by using anti-CD16/CD32 mAb (2.4G2) before surface staining with the indicated Abs (purchased from BD Biosciences or eBioscience). Samples were acquired on an LSR II flow spectrometer (BD Biosciences) and analyzed using FlowJo software (Tree Star). Statistical analysis Statistical differences in the percentages of NK cells from wild-type and B2mϪ/Ϫ mice making IFN-␥ ex vivo after stimulation with plate-bound anti-Ly49H Abs were determined by using the two-tailed unpaired Stu- Downloaded from dent’s t test. Results and Discussion Phenotypic similarities between NK cells from wild-type and B2mϪ/Ϫ mice

According to the “licensing” or “disarming” models of develop- http://www.jimmunol.org/ ment, NK cells that mature in the absence of MHC class I might show phenotypic abnormalities. Others have noticed subtle or no differences in maturation markers (such as Mac-1 Ϫ Ϫ Ϫ/Ϫ or CD43) on NK cell subsets between wild-type and B2m / FIGURE 1. Phenotype of NK cells from wild-type and B2m mice. a, Percentages of total NK cells and NK cell subsets from the spleens of wild- mice (8, 15). We examined survival and activation markers and Ϫ Ϫ type and B2m / mice were compared. Left plots were gated on total live expression of the activating receptors Ly49D and Ly49H on pe- cells in the spleen. Right plots were gated on total NK cells (CD3Ϫ, NK1.1ϩ) Ϫ/Ϫ ripheral NK cells from wild-type and B2m mice. Although Ϫ/Ϫ ϩ in the spleen. b, NK cells from wild-type (solid lines) and B2m (dotted the percentage of CD8 T cells was severely diminished in lines) mice were compared for expression of different cell surface markers. by guest on September 24, 2021 Ϫ Ϫ B2m / mice compared with wild-type mice, overall NK cell Data are representative of three independent experiments with 2–3 mice per numbers showed no statistically significant differences in the group analyzed in each independent experiment. spleen (p Ͼ 0.05) (Fig. 1a). The percentages of NK cells expressing the activating Ly49D, Ly49H, and NKG2D and the Ϫ Ϫ amounts of these receptors were also not statistically different B2m / NK cells (p Ͻ 0.01) (Fig. 2a). In concordance with Ϫ Ϫ Ϫ Ϫ on NK cells from wild-type and B2m / mice (p Ͼ 0.05) (Fig. these findings, prior studies have reported that B2m / NK 1). Furthermore, the survival and activation marker phenotypes cells mediated slightly less lytic activity against NK-sensitive Ϫ Ϫ of NK cells from both wild-type and B2m / mice were com- Yac-1 cell targets and produced less IFN-␥ when stimulated in parable (Fig. 1b). In particular, the expression of CD122, vitro with anti-NK1.1 or anti-Ly49D compared with wild-type CD25, CD62L, CD27, Ly6C, and CD69 markers, which have NK cells (3, 4). been correlated with NK cell homeostasis and activation, was Within 48 h after infection of B6 mice with MCMV, all Ϫ Ϫ Ϫ ϩ comparable on wild-type and B2m / NK cells. The notable NK cells, including both Ly49H and Ly49H NK cells, exception is killer cell lectin-like receptor G1 (KLRG1), which become stimulated, as documented by up-regulation of ac- Ϫ Ϫ was on fewer NK cells from B2m / compared with wild-type tivation Ags and production of IFN-␥. This global and non- mice (Fig. 1b), as previously reported (16, 17). Overall, other specific MCMV-induced activation, likely a consequence of than the previously described effects of MHC class I on expres- the production of type I IFN and proinflammatory cytokines sion of certain inhibitory Ly49 receptors (18–20), there are few such as IL-12 and IL-18 (23), is followed by the specific ex- Ϫ Ϫ ϩ phenotypic differences between wild-type and B2m / NK pansion of Ly49H NK cells. To evaluate the function of Ϫ Ϫ cells, demonstrating that NK cell development is largely intact B2m / NK cells in a more physiological context, we in- Ϫ Ϫ and there is no evidence for chronic activation of NK cells in the fected wild-type and B2m / mice with MCMV and mea- absence of MHC class I. sured IFN-␥ and the lysosomal-associated membrane pro-

Ϫ/Ϫ tein LAMP-1 (a measure of degranulation) in NK cells ex Functional similarities of wild-type and B2m NK cells vivo at 36 h postinfection. Again, both wild-type and Ϫ Ϫ We compared the ability of NK cells from wild-type and B2m / NK cells responded robustly and to a very compa- Ϫ Ϫ B2m / mice to produce IFN-␥ ex vivo in response to plate- rable magnitude (Fig. 2b). In concordance with our in vivo bound Abs against the activating receptor Ly49H, the receptor findings, Yokoyama and Kim previously reported that cul- Ϫ Ϫ for the MCMV m157 glycoprotein (21, 22). Both wild-type turing NK cells in vitro in IL-12 permitted B2m / NK cells Ϫ Ϫ and B2m / NK cells produced similar amounts of IFN-␥; to make IFN-␥ at levels comparable to that of wild-type NK ϩ however, ϳ2-fold more wild-type NK cells made IFN-␥ than cells (15). The expansion of Ly49H NK cells following The Journal of Immunology 7455

FIGURE 2. Function of NK cells from wild-type and B2mϪ/Ϫ mice. a, Plots show percentage of NK cells from wild-type and B2mϪ/Ϫ mice that produce IFN-␥ in response to stimulation by anti-Ly49H Abs. b, Wild-type and B2mϪ/Ϫ mice were infected with MCMV and NK cells were analyzed at 36 h postinfection for intracellular IFN-␥ production and LAMP-1 expression. Top panels show percentages of IFN-␥ production within the Ly49Hϩ and Ly49HϪ NK cell populations. c, Wild-type and B2mϪ/Ϫ mice were infected with MCMV and NK cells were analyzed at 8 days postinfection (PI) (compared with uninfected mice) for expression of Ly49H and KLRG1. d, Graph shows the percentage of ϩ Ly49H NK cells in the spleens and livers Downloaded from of uninfected and day 8 (d8)-postinfection wild-type (WT) and B2mϪ/Ϫ mice. Error bars on graph display SEM (n ϭ 3–5) and data are representative of three independent experiments with 3–5 mice per group in each independent experiment. http://www.jimmunol.org/

MCMV infection was similar between wild-type and 3 mo postreconstitution the 1:1 chimeras were found at a 3:1 Ϫ Ϫ B2m / mice in the spleen and liver (Fig. 2, c and d). Fur- frequency in favor of wild-type hematopoietic cells, and the Ϫ Ϫ thermore, although KLRG1 was initially expressed at a lower 10:1 chimeras contained almost no B2m / cells (Fig. 3a). Ϫ Ϫ frequency on B2m / NK cells, after MCMV infection, Thus, while tolerance to “missing self” was initially established Ϫ/Ϫ KLRG1 was comparably up-regulated on both B2m and by guest on September 24, 2021 wild-type NK cells in liver and spleen (Fig. 2c). Together, Ϫ Ϫ these data suggest that NK cells from B2m / mice are ca- pable of robustly responding and functioning during a viral infection. ϩ Ϫ Ϫ Our findings that Ly49H NK cells from B2m / mice can produce cytokines and expand provide a mechanism for prior studies demonstrating that NK cell-mediated control of Ϫ Ϫ MCMV replication is equivalent in wild-type and B2m / mice (11, 12). Thus, although NK cells from mice lacking MHC class I are less responsive when assayed in vitro, these NK cells developing in the absence of MHC class I respond robustly and efficiently when challenged with a relevant pathogen in vivo.

B2mϪ/Ϫ cells gradually decline in chimeric wild-type:B2mϪ/Ϫ mice Wu and Raulet previously reported that tolerance to “missing Ϫ Ϫ self” was induced in wild-type NK cells against B2m / hematopoietic cells in mixed bone marrow chimeras reconstituted Ϫ/Ϫ with a mixture of wild-type and B2m hematopoietic stem Ϫ Ϫ Ϫ Ϫ FIGURE 3. Gradual loss of B2m / cells in mixed wild-type:B2m / cells (24). Similarly, we generated chimeras by NK cell-deplet- ϩ chimeric mice. a, Ratios of 1:1 (top panels) and 10:1 (lower panels) wild-type ing and lethally irradiating congenic B6 mice (CD45.1 ϫ Ϫ/Ϫ ϩ (WT):B2m chimeric mice were generated. Left density plots show per- CD45.2 ), followed by reconstitution with a mixture of wild- centages of wild-type (CD45.1ϩ) and B2mϪ/Ϫ (CD45.2ϩ) bone marrow ϩ Ϫ Ϫ ϩ type (CD45.1 ) and B2m / (CD45.2 ) bone marrow stem cells before transfer into irradiated recipient mice. Histogram plot shows Ϫ Ϫ cells, which had been depleted of NK cells, at ratios of 1:1 and H-2Kb staining performed on wild-type (solid line) and B2m / (dotted line) cells. Middle and right density plots show percentages of wild-type and 10:1 (Fig. 3a). Consistent with previous findings (24), we ob- Ϫ/Ϫ Ϫ/Ϫ B2m cells at 5 wk and 3 mo postirradiation, respectively. b, Graphs show served that both wild-type and B2m hematopoietic cells percentage of B2mϪ/Ϫ cells (CD45.2ϩ) at various time points postirradiation in populated the irradiated recipients at 5 wk postreconstitution. 1:1 chimeras (left graph) and 10:1 chimeras (right graph). Error bars on graphs dis- However, the wild-type cells were detected at a higher percent- play SEM (n ϭ 3–5 at each time point) and data are representative of two indepen- age than the original input frequency (Fig. 3a). Surprisingly, by dent experiments with 3–5 mice per time point. 7456 CUTTING EDGE: BREAKING TOLERANCE TO MISSING SELF

ing cells not expressing H-2d in vivo, the tolerance was broken when the transgene-bearing NK cells from these animals were cultured with IL-2 in vitro and assayed for their ability to kill targets lacking H-2d (25). Thus, as in the mixed bone marrow chimeric mice, NK cell tolerance to “missing self” in these H-2d transgenic B6 mice was not permanent and could be broken by NK cell activation. Concluding remarks These findings raise several important questions. What are the b molecular mechanisms of peripheral NK cell tolerance of “missing self” in the steady state (noninflammatory environment)? What accounts for NK cell-mediated rejection of MHC class I-deficient cells during inflammation, when tolerance is broken? When wild-type NK cells in MHC class I-deficient animals do become activated during inflammation, do these animals become autoimmune? Lastly, what are the implications to

the “licensing” or “disarming” of NK cells if self-tolerance can Downloaded from FIGURE 4. Rapid rejection of B2mϪ/Ϫ cells in chimeric mice following in- be easily broken during inflammation? Determining the precise fection. a, Upper plots show percentages of wild-type (CD45.1ϩ) and B2mϪ/Ϫ developmental and peripheral tolerance mechanisms at work in (CD45.2ϩ) cells for 1 wk in mixed wild-type:B2mϪ/Ϫ chimeric mice following NK cells will aid in our understanding of how immune re- Ϫ/Ϫ MCMV infection. Lower plots show percentages of wild-type and B2m cells sponses are regulated and the potential consequences of induc- for 2 mo in mice treated with NK cell-depleting (NK-depl) Abs before MCMV Ϫ Ϫ ϩ ing inflammation. infection. b, Graphs show percentage of B2m / cells (CD45.2 ) at various time points in mice infected with MCMV (left graph) and mice treated with NK http://www.jimmunol.org/ cell-depleting Abs before MCMV infection (right graph). Insets show percent- Acknowledgments ages of CD3Ϫ, NK1.1ϩ cells at day 7 postinfection, demonstrating the efficacy We thank the Lanier lab for insightful comments and helpful discussions. of NK cell-depleting Abs. Error bars on graphs display SEM (n ϭ 3–5 at each time point) and data are representative of two independent experiments with Disclosures 3–5 mice per time point. The authors have no financial conflict of interest. References 1. Ljunggren, H. G., and K. Karre. 1990. In search of the ‘missing self’: MHC molecules in these mixed bone marrow chimeric mice, longitudinal stud- and NK cell recognition. Immunol. Today 11: 237–244. by guest on September 24, 2021 2. Bix, M., N. S. Liao, M. Zijlstra, J. Loring, R. Jaenisch, and D. Raulet. 1991. Rejection ies of these mice revealed a slow but steady loss of cells lacking of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice. Na- MHC class I (Fig. 3b). These findings suggest the possibility ture 349: 329–331. Ϫ/Ϫ 3. Hoglund, P., C. Ohlen, E. Carbone, L. Franksson, H. G. Ljunggren, A. Latour, that either the B2m hematopoietic cells were less fit than ␤ ␤ Ϫ B. Koller, and K. Karre. 1991. Recognition of 2-microglobulin-negative ( 2m )T- ␤ Ϫ the wild-type hematopoietic cells or, alternatively, that these cell blasts by natural killer cells from normal but not from 2m mice: nonrespon- Ϫ Ϫ ␤ Ϫ / siveness controlled by 2m bone marrow in chimeric mice. Proc. Natl. Acad. Sci. B2m cells were being actively eliminated by the wild-type USA 88: 10332–10336. NK cells. 4. Liao, N. S., M. Bix, M. Zijlstra, R. Jaenisch, and D. Raulet. 1991. MHC class I de- ficiency: susceptibility to natural killer (NK) cells and impaired NK activity. Science B2mϪ/Ϫ cells are rapidly rejected by wild-type NK cells in chimeric 253: 199–202. 5. Ljunggren, H. G., L. Van Kaer, H. L. Ploegh, and S. Tonegawa. 1994. Altered natural mice following viral infection killer cell repertoire in Tap-1 mutant mice. Proc. Natl. Acad. Sci. USA 91: Ϫ/Ϫ 6520–6524. When we infected the mixed wild-type:B2m bone mar- 6. Grigoriadou, K., C. Menard, B. Perarnau, and F. A. Lemonnier. 1999. MHC class Ia row chimeric mice with MCMV, we observed a precipitous molecules alone control NK-mediated bone marrow graft rejection. Eur. J. Immunol. Ϫ/Ϫ ϩ 29: 3683–3690. drop in B2m cell numbers (CD45.2 ) over the course of 7. Hoglund, P., R. Glas, C. Menard, A. Kase, M. H. Johansson, L. Franksson, ␤ 1 wk (Fig. 4). NK cells mediated this rapid rejection of F. Lemmonier, and K. Karre. 1998. 2-Microglobulin-deficient NK cells show in- Ϫ Ϫ B2m / cells, because when we treated chimeric mice with a creased sensitivity to MHC class I-mediated inhibition, but self tolerance does not Ϫ/Ϫ depend upon target cell expression of H-2Kb and Db heavy chains. Eur. J. Immunol. NK cell-depleting Ab, B2m cells were maintained (Fig. 28: 370–378. 4). Thus, although tolerance to “missing self” can be estab- 8. Fernandez, N. C., E. Treiner, R. E. Vance, A. M. Jamieson, S. Lemieux, and D. H. Raulet. 2005. A subset of natural killer cells achieves self-tolerance without lished by generating unresponsive or “disarmed” NK cells expressing inhibitory receptors specific for self-MHC molecules. Blood 105: that develop in the presence of MHC class I-deficient hema- 4416–4423. 9. Kim, S., J. Poursine-Laurent, S. M. Truscott, L. Lybarger, Y. J. Song, L. Yang, topoietic cells, this tolerance is easily broken during inflam- A. R. French, J. B. Sunwoo, S. Lemieux, T. H. Hansen, and W. M. Yokoyama. 2005. mation, leading to the rapid destruction of hematopoietic Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436: 709–713. cells lacking MHC class I. 10. Denkers, E. Y., R. T. Gazzinelli, D. Martin, and A. Sher. 1993. Emergence of These observations suggest that the NK cell tolerance of NK1.1ϩ cells as effectors of IFN-␥ dependent immunity to Toxoplasma gondii in “missing self” is actively maintained, not permanent, and can be MHC class I-deficient mice. J. Exp. Med. 178: 1465–1472. 11. Polic, B., S. Jonjic, I. Pavic, I. Crnkovic, I. Zorica, H. Hengel, P. Lucin, and readily overcome via activation of the NK cells by a physiolog- U. H. Koszinowski. 1996. Lack of MHC class I complex expression has no effect ical stimulus, i.e., viral infection. Similarly, Karre and col- on spread and control of cytomegalovirus infection in vivo. J. Gen. Virol. 77: d 217–225. leagues reported that NK cells developing in a H-2 transgenic 12. Tay, C. H., R. M. Welsh, and R. R. Brutkiewicz. 1995. NK cell response to viral d ␤ B6 mouse, where H-2 was expressed in a mosaic pattern in infections in 2-microglobulin-deficient mice. J. Immunol. 154: 780–789. 13. Sun, J. C., S. M. Lehar, and M. J. Bevan. 2006. Augmented IL-7 signaling during viral these animals, are tolerant (25). Although the NK cells in these infection drives greater expansion of effector T cells but does not enhance memory. d mice expressing the H-2 transgene were tolerant of surround- J. Immunol. 177: 4458–4463. The Journal of Immunology 7457

14. Sun, J. C., and L. L. Lanier. 2008. Tolerance of NK cells encountering their viral ceptors on natural killer cells from MHC class I-deficient mice. J. Immunol. 158: ligand during development. J. Exp. Med. 205: 1819–1828. 3174–3180. 15. Yokoyama, W. M., and S. Kim. 2006. Licensing of natural killer cells by self-major 21. Arase, H., E. S. Mocarski, A. E. Campbell, A. B. Hill, and L. L. Lanier. 2002. Direct histocompatibility complex class I. Immunol. Rev. 214: 143–154. recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 16. Corral, L., T. Hanke, R. E. Vance, D. Cado, and D. H. Raulet. 2000. NK cell expres- 296: 1323–1326. sion of the killer cell lectin-like receptor G1 (KLRG1), the mouse homolog of MAFA, 22. Smith, H. R., J. W. Heusel, I. K. Mehta, S. Kim, B. G. Dorner, O. V. Naidenko, is modulated by MHC class I molecules. Eur. J. Immunol. 30: 920–930. K. Iizuka, H. Furukawa, D. L. Beckman, J. T. Pingel, et al. 2002. Recognition of a 17. Robbins, S. H., M. S. Tessmer, L. Van Kaer, and L. Brossay. 2005. Direct effects of virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl. Acad. Sci. T-bet and MHC class I expression, but not STAT1, on peripheral NK cell maturation. USA 99: 8826–8831. Eur. J. Immunol. 35: 757–765. 23. Biron, C. A., K. B. Nguyen, G. C. Pien, L. P. Cousens, and T. P. Salazar-Mather. 18. Dorfman, J. R., J. Zerrahn, M. C. Coles, and D. H. Raulet. 1997. The basis for self- 1999. Natural killer cells in antiviral defense: function and regulation by innate cyto- ␤ Ϫ Ϫ tolerance of natural killer cells in 2-microglobulin and TAP-1 mice. J. Immunol. kines. Annu. Rev. Immunol. 17: 189–220. 159: 5219–5225. 24. Wu, M. F., and D. H. Raulet. 1997. Class I-deficient hemopoietic cells and nonhe- 19. Held, W., J. R. Dorfman, M. F. Wu, and D. H. Raulet. 1996. Major histocompati- mopoietic cells dominantly induce unresponsiveness of natural killer cells to class I- bility complex class I-dependent skewing of the natural killer cell Ly49 receptor rep- deficient bone marrow cell grafts. J. Immunol. 158: 1628–1633. ertoire. Eur. J. Immunol. 26: 2286–2292. 25. Johansson, M. H., C. Bieberich, G. Jay, K. Karre, and P. Hoglund. 1997. Natural 20. Salcedo, M., A. D. Diehl, M. Y. Olsson-Alheim, J. Sundback, L. Van Kaer, killer cell tolerance in mice with mosaic expression of major histocompatibility com- K. Karre, and H. G. Ljunggren. 1997. Altered expression of Ly49 inhibitory re- plex class I transgene. J. Exp. Med. 186: 353–364. Downloaded from http://www.jimmunol.org/ by guest on September 24, 2021