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The Journal of Immunology, 1999, 162: 3753-3756.
Copyright © 1999 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: LFA-1 Is Required for Liver NK1.1+TCR{alpha}ß+ Cell Development: Evidence That Liver NK1.1+TCR{alpha}ß+ Cells Originate from Multiple Pathways1

Toshiaki Ohteki2,*,{ddagger}, Chikako Maki{ddagger}, Shigeo Koyasu{ddagger}, Tak W. Mak*,{dagger} and Pamela S. Ohashi*

* Departments of Medical Biophysics and Immunology, Ontario Cancer Institute, Toronto, Ontario, Canada; {dagger} Amgen Institute, Toronto, Ontario, Canada; and {ddagger} Department of Immunology, Keio University School of Medicine, Tokyo, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Using mice deficient for LFA-1, CD44, and ICAM-1, we examined the role of these adhesion molecules in NK1.1+TCR{alpha}ß+ (NKT) cell development. Although no defect in NKT cell development was observed in CD44-/- and ICAM-1-/- mice, a dramatic reduction of liver NKT cells was observed in LFA-1-/- mice. Normal numbers of NKT cells were present in other lymphoid organs in LFA-1-/- mice. When LFA-1-/- splenocytes were injected i.v. into wild-type mice, the frequency of NKT cells among donor-derived cells in the recipient liver was normal. In contrast, when LFA-1-/- bone marrow (BM) cells were injected i.v. into irradiated wild-type mice, the frequency of liver NKT cells was significantly lower than that of mice injected with wild-type BM cells. Collectively, these data indicate that LFA-1 is required for the development of liver NKT cells, rather than the migration to and/or subsequent establishment of mature NKT cells in the liver.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The NK1.1+TCR{alpha}ß+ (NKT)3 cells have recently been classified as a unique lymphocyte subset based on the expression of NKR-P1 and Ly-49 family, as well as the IL-2Rß/15Rß-chain (1, 2). In mice, the majority of NKT cells express canonical V{alpha}14-J{alpha}15/Vß8, Vß7, or Vß2 gene segments (3, 4, 5, 6) that interact with lipid ligands, such as ceramides (7) or glycosylphosphatidylinositols (8) presented by CD1d, an MHC class Ib-like molecule (9, 10, 11, 12). Recent studies have suggested the importance of NKT cells as effector cells in tumor rejection (13, 14, 15), IL-4 production (6, 16, 17), and as regulatory cells in autoimmune diseases (18, 19, 20, 21).

LFA-1 (CD11a/CD18) is a cell adhesion molecule that belongs to the integrin family. It is expressed on a variety of hematolymphoid cells, such as T cells, B cells, granulocytes, dendritic cells, and macrophages (22, 23). The natural ligands for LFA-1 are ICAM-1, -2, and -3, which are expressed by endothelial cells and APCs. LFA-1/ligand interactions are important in lymphocyte recirculation and inflammation as well as T cell activation (22, 23). Using CD11a-deficient mice (referred to as LFA-1-/- mice hereafter), we examined the role of LFA-1/ligand interactions on NKT cell circulation/maturation and observed a selective reduction of liver NKT cells in LFA-1-/- mice. Our studies further revealed that the NKT cells require LFA-1 molecules during development rather than migration to the liver. In addition, the cell surface phenotype of liver NKT cells in LFA-1-/- mice was distinct from wild-type liver NKT cells but rather similar to those of splenic NKT cells in terms of Ly-49 expression, suggesting that the residual liver NKT cells in LFA-1-/- mice are immigrants from other sites, such as the spleen.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

C57BL/6 mice deficient for CD11a (24) and CD44 (25) have been reported previously. C57BL/6 mice deficient for ICAM-1 (26) were purchased from The Jackson Laboratory (Bar Harbor, ME). B6.SJL-ptprca (B6.SJL hereafter) mice, which are C57BL/6 congenic at the CD45 locus, were purchased from Taconic (Germantown, NY). All mice were maintained in our specific pathogen-free animal facility according to institutional guidelines, and experiments were done at 6–12 wk of age.

Cell preparation

Mononuclear cells (MNC) from the thymus, liver, spleen, lymph nodes, and bone marrow (BM) were obtained by standard methods, as described (5).

Abs and flow cytometric analysis

The following mAbs were purchased from PharMingen (San Diego, CA): M1/69-FITC (anti-heat stable Ag (HSA); H57-597-FITC, -phycoerythrin (PE) (anti-TCRß); TM-ß1-PE (anti-IL-2Rß); PK136-PE, -biotin (anti-NK1.1); 27D-biotin (anti-LFA-1); IM7-biotin (anti-CD44); A1-biotin (anti-Ly-49A); SW-5E6-biotin (anti-Ly-49C/I); 104-biotin (anti-CD45.2); and A20-biotin (anti-CD45.1). A mAb 2.4G2 (anti-Fc{gamma}RII/III) was purified from hybridoma culture supernatants. Biotinylated mAbs were detected with streptavidin Red670 (Life Technologies, Gaithersburg, MD). Cells (1–2 x 106) were stained in PBS-2% FCS containing 10 µg/ml 2.4G2 to block Fc receptor-mediated nonspecific binding, washed, and analyzed on a FACScan using the CELLQuest program (Becton Dickinson, San Jose, CA).

Adoptive transfer experiments

Spleen cells were obtained from either C57BL/6 mice, LFA-1-deficient mice, or B6.SJL mice, and CD8-B220- cells were further purified by magnetic cell separation system (Miltenyi Biotec, Auburn, CA). A total of 5 x 106 cells were injected i.v. into B6.SJL mice or LFA-1-deficient mice. After 20–24 h, liver and spleen MNC were harvested from the recipient mice and stained with H57-597-FITC (anti-TCRß), PK136-PE (anti-NK1.1), and 104-biotin (anti-CD45.2) or A20-biotin (anti-CD45.1), followed by streptavidin Red670 (Life Technologies). Donor-derived cells were gated according to the staining patterns of CD45 and analyzed for other cell surface molecules.

Radiation BM chimeras

To make reciprocal chimeras between LFA-1-deficient and B6.SJL mice, recipients were lethally irradiated (950 rad, 137Cs source) and reconstituted 1 day later with 15–20 x 106 BM cells. Chimerism was monitored by staining of blood MNC with mAbs against TCRß, CD45R/B220, and CD45.2 or CD45.1. Chimeras were usually sacrificed 7 wk after reconstitution and analyzed for donor-derived cells.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Selective reduction of liver NKT cell subset in LFA-1-/- mice

Physiological roles of LFA-1, CD44, and ICAM-1 molecules expressed on NKT cells remains unclear. Therefore, we examined the NKT cells from LFA-1-/-, CD44-/-, and ICAM-1-/- mice by flow cytometric analysis and found that the proportion and number of liver NKT cells in LFA-1-/- mice were lower than those of wild-type mice (Fig. 1Go, data not shown). CD44high TCR{alpha}ß+ T cells were also decreased, suggesting that the profound reduction of NKT cells in LFA-1-/- mice was not simply due to the loss of NK1.1 molecules from the cell surface. Unlike LFA-1-/- mice, CD44-/- and ICAM-1-/- mice had normal numbers of NKT cells in the liver. Since NKT cells are present not only in the liver but also in other lymphoid organs (1, 2), we further examined the thymus, spleen, and BM of LFA-1-/- mice (Fig. 2Go). Contrary to the liver, normal numbers of NKT cells were present in those organs, indicating that the reduction of NKT cells in LFA-1-/- mice was restricted to the liver.



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  		FIGURE 1. Reduction of liver NKT cells in LFA-1-/- mice. Liver MNC were isolated from the indicated mice and stained with H57-597-FITC (anti-TCRß), PK136-PE (anti-NK1.1), and IM7-PE (anti-CD44). Cells in the upper right quadrant are NKT cells.

 


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  		FIGURE 2. Reduction of NKT cells is restricted to the liver in LFA-1-/- mice. MNC were isolated from the indicated organs and stained with H57-597-FITC (anti-TCRß) and PK136-PE (anti-NK1.1).

 
LFA-1-deficient NKT cells can migrate to the liver

As cell adhesion molecules including LFA-1 play important roles in lymphocyte recirculation (22, 23), it is possible that the interaction of LFA-1 with its natural ligand(s) is involved in migration of NKT cells to the liver. To examine this possibility, we used a lymphocyte migration assay (27) in which 5 x 106 splenic CD8-B220- cells containing NKT cells, NK cells, and conventional T cells were injected into recipient mice. After 24 h, the frequency of NKT cells in various organs was examined using anti-CD45.1 and anti-CD45.2 mAbs to distinguish donor-derived and host NKT cells. As shown in Fig. 3GoA, the frequency of LFA-1-deficient NKT cells was comparable to that of wild-type NKT cells in the liver of the B6.SJL host. In addition, wild-type NKT cells migrated to the liver in LFA-1-deficient host animals in a manner similar to NK cells and conventional T cells (Fig. 3GoA and data not shown). These results indicate that NKT cells were capable of migrating into the liver in the absence of LFA-1.



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  		FIGURE 3. A, LFA-1-independent migration of NKT cells into the liver. LFA-1-deficient or wild-type CD8-B220- spleen cells were injected into B6.SJL or LFA-1-deficient mice on a C57BL/6 background. On day 1, donor derived cells present in the liver and spleen were gated according to the staining by donor type anti-CD45 mAb and further analyzed for TCRß and NK1.1. Data are presented as percent NKT cells among donor-derived MNC. B, LFA-1 molecules on hematopoietic cells are required for the development of liver NKT cells. Irradiation BM chimeras were made between LFA-1-deficient and wild-type mice. Chimerism was determined by staining with mAb against either CD45.1 (B6.SJL into LFA-1-/-) or CD45.2 (LFA-1-/- into B6.SJL), and cells were analyzed after excluding host-derived cells. Data are presented as percent NKT cells among donor-derived MNC.

 
LFA-1 molecules on hematopoietic cells control the development of liver NKT cells

The mechanism underlying the reduction of NKT cells in the liver of LFA-1-deficient mice was further investigated in radiation BM chimeras. As expected from the above results (Figs. 1Go and 2Go), NK cells and conventional T cells developed normally in lethally irradiated wild-type hosts grafted with LFA1-/- BM or LFA1-/- hosts grafted with wild-type BM (data not shown). In contrast, the development of NKT cells in the liver of wild-type hosts grafted with LFA-1-deficient BM was significantly impaired, indicating the importance of LFA-1 on the donor BM cells (Fig. 3GoB). Furthermore, development of the liver but not splenic NKT cells strictly required the presence of LFA-1+ cells of donor but not host origin. These data indicate that the expression of LFA-1 molecules on radiosensitive hematopoietic cells is required for the development of liver NKT cells.

Expression patterns of Ly-49 on liver NKT cells in LFA-1-deficient mice are similar to those of splenic NKT cells

The Ly-49 family is comprised of nine members encoding homodimeric C-type lectin-like receptors that interact with specific alleles of MHC class I molecules (28). A recent report showed that the proportion of NKT cells expressing Ly-49A or Ly-49C/I genes was higher in the thymus than in the liver (29). Thus, we examined Ly-49 expression patterns on NKT cells in wild-type and LFA-1-deficient mice. Consistent with the previous report (29), the proportion of NKT cells expressing Ly-49A and Ly-49C/I was higher in the thymus than in the liver of wild-type mice (Fig. 4Go). The frequency of liver NKT cells in LFA-1-deficient mice that express Ly-49A or Ly-49C/I receptors was higher than wild-type liver NKT cells, and the Ly-49 expression patterns were similar to those of splenic NKT cells (Fig. 4Go). These data suggest that liver NKT cells present in LFA-1-deficient mice have migrated from the spleen. Consistent with this interpretation, splenic NKT cells were able to migrate into the liver in an LFA-1-independent manner (Fig. 3GoA). In addition, liver NKT cells in LFA-1-deficient mice exhibited a TCR repertoire that was highly skewed to Vß8 as observed for wild-type NKT cells (Fig. 4Go).



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  		FIGURE 4. Abnormal expression patterns of Ly-49 on liver NKT cells in LFA-1-deficient mice. MNC obtained from the liver, thymus, and spleen of wild-type and LFA-1-deficient mice were stained with mAbs against TCRß, NK1.1, and Ly-49A, -C/I or Vß8. Mean percentages (SD) of Ly-49A, -C/I, or Vß8 among NKT cells are indicated.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We present here a selective reduction of NKT cells in the liver but not in the thymus, spleen, and BM of LFA-1-deficient mice. Our results showed that the LFA-1 is required for the development of liver NKT cells rather than for migration to and subsequent establishment in the liver.

Reports have suggested that NKT cell maturation is accompanied by changes in the Ly-49 receptor repertoire, and this may be necessary for the complete and/or effective maturation process in the thymus and their subsequent migration to peripheral organs, such as the liver (29). The fact that thymic NKT cells in LFA-1-deficient mice showed a "splenic-type" expression pattern of Ly-49 receptors may be a consequence of the lack of LFA-1 during NKT cell development. The lack of LFA-1 may affect the Ly-49 repertoire formation in the thymus, and such impaired Ly-49 repertoire modification during NKT cell development may cause the reduction of liver NKT cells in LFA-1-deficient mice. However, no alteration was observed in the splenic NKT cells in LFA-1-deficient mice (Figs. 2Go and 4Go) that are widely accepted to originate in the thymus (27). These splenic NKT cells showed normal "splenic-type" expression patterns of Ly-49 receptors in the absence of LFA-1. These results do not seem to support the above scenario. Alternatively, the liver NKT cells in the LFA-1-deficient mice bearing "splenic-type" Ly-49 receptors may be immigrants from other organs, such as the spleen. In wild-type mice, the NKT cell population bearing "liver-type" Ly-49 receptors, characterized by the lack of Ly49A, -C, and -I, is a major subset in the liver. This subset is absent in LFA-1-deficient mice, suggesting that these "liver-type" NKT cells are generated in situ in the liver. The mechanism underlying how LFA-1 is involved in the development of liver NKT cells remains unclear. Since LFA-1 is believed to play an important role in lymphocyte recirculation rather than lymphocyte development, it is possible that interaction between LFA-1 and its ligands is crucial for the relevant precursor cells to migrate to the liver at an earlier stage of NKT cell development.

Evidence suggests that NKT cells develop in the thymus and migrate to peripheral organs. NKT cells develop in fetal thymic organ cultures (30), and studies have shown that thymic NKT cells can migrate to the spleen and the liver (27). Furthermore, neonatal thymus grafts implanted in congenitally athymic mice give rise to NKT cells in the recipient organs (31). However, the NKT cells expressing the canonical V{alpha}14-J{alpha}281 TCR are detected in BM, spleen, and liver of nude mice (13, 32, 33, 34), and reconstitution of adult thymectomized irradiated mice with syngeneic BM cells gives rise to NKT cells in the recipient organs, including the liver (35), suggesting that some NKT cells can develop extrathymically. Collectively, accumulating evidence, including ours, suggests that liver NKT cells may originate from both thymic and extrathymic pathways, and different NKT cell subsets require different molecular interactions during development.


   Acknowledgments
 
We thank Dr. Goichi Matsumoto (Kanagawa Dental College, Yokosuka, Japan) for providing LFA-1-/- mice.


   Footnotes
 
1 This work was supported by the Medical Research Council of Canada. T.O. is supported by KANAE Foundation for Life and Socio-Medical Science. S.K. is supported by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan and a Keio University Special Grant-in-Aid for Innovative Collaborative Research Projects. P.S.O. is supported by a Medical Research Council scholarship. Back

2 Address correspondence and reprint requests to Dr. Toshiaki Ohteki, Department of Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail address: Back

3 Abbreviations used in this paper: NKT, NK1.1+TCR{alpha}ß+; BM, bone marrow; MNC, mononuclear cell; PE, phycoerythrin. Back

Received for publication November 19, 1998. Accepted for publication January 19, 1999.


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