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The Journal of Immunology, 2004, 173: 2236-2240.
Copyright © 2004 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Differential Roles for Phosphoinositide 3-Kinases, p110{gamma} and p110{delta}, in Lymphocyte Chemotaxis and Homing1

Karin Reif2,*, Klaus Okkenhaug{dagger}, Takehiko Sasaki{ddagger}, Joseph M. Penninger§, Bart Vanhaesebroeck and Jason G. Cyster3,*

* Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; {dagger} Molecular Immunology Programme, The Babraham Institute, Cambridge, United Kingdom; {ddagger} The 21st Century Center of Excellence Program, Akita University School of Medicine and Precursory Research for Embryonic Science and Technology, Hondo, Akita, Japan; § Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria; and Cell Signalling Group, Ludwig Institute for Cancer Research, and Department of Biochemistry and Molecular Biology, University College, London, United Kingdom.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Despite the established role for PI3Ks in cell migration, the PI3Ks involved in lymphocyte chemotaxis are poorly defined. In this study, we report that p110{gamma}-deficient T cells, but not B cells, show reduced chemotactic responses to the lymphoid chemokines, CCL19, CCL21, and CXCL12. As B cell and T cell chemotactic responses were both sensitive to the general PI3K inhibitors, wortmannin (WMN) and LY294002, we explored whether B cell responses were affected in mice lacking p110{delta}, a major PI3K isoform in lymphocytes. B cells deficient in p110{delta} showed diminished chemotactic responses, especially to CXCL13. Adoptive transfer experiments with WMN-treated wild-type B cells and with p110{delta}-deficient B cells revealed diminished homing to Peyer’s patches and splenic white pulp cords. WMN selectively inhibited CXCR5-dependent B cell homing to Peyer’s patches. These observations establish that p110{gamma} and p110{delta} function in lymphocyte chemotaxis, and show differential roles for PI3K family members in B and T cell migration.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The process of immune surveillance depends on chemokine-directed migration of lymphocytes into and within lymphoid organs. Chemokines important for these events include: CXCL13 (BLC), a ligand for CXCR5, that guides B cells to lymphoid follicles; CCL19 (ELC) and CCL21 (SLC, 6Ckine), ligands for CCR7, that guide cells to lymphoid organ T zones; and CXCL12 (SDF1), the ligand for CXCR4, that has a broad spectrum of functions, including roles in B cell homing (1, 2).

Efforts to dissect the mechanisms of eukaryotic cell chemotaxis toward attractants acting via G protein-coupled receptors, principally performed in neutrophils and in the slime mold Dictyostelium discoideum, have established an important role for PI3Ks (3, 4). PI3Ks function to relay the chemoattractant gradient to the inside of the cell, generating high concentrations of phosphatidylinositol 3,4,5-trisphosphate at the leading edge (3, 4). Consistent with this, neutrophils and macrophages from mice lacking p110{gamma}, a class IB PI3K that couples to heterotrimeric G proteins, are poorly responsive to chemoattractants (reviewed in Refs. 5 , 6). By contrast, lymphocyte migration was not reported to be affected in these animals. However, studies with pharmacological inhibitors of PI3K, wortmannin (WMN)4 and LY294002, and with dominant-negative forms of PI3K have provided evidence that PI3K contributes to lymphocyte chemotactic responses (2).

In this study, we examined the PI3K requirement for naive lymphocyte responses to lymphoid chemokines. We show that p110{gamma} functions in T cell chemotaxis and that a class IA PI3K, p110{delta}, is required for maximal B cell chemotaxis to CXCL13 and for B cell homing to Peyer’s patches (PPs) and to the splenic white pulp.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice and bone marrow chimeras

CXCR5–/– mice and IgHEL-transgenic mice of the MD4 line were on a C57BL/6 (B6) background (7). IghaThy1aGpi1a B6 mice (termed Igha) were from The Jackson Laboratory (Bar Harbor, ME). B6 or B6-CD45.1 (Ly5.2) mice were from Charles River Laboratories (Wilmington, MA) or a University of California colony (San Francisco, CA). The mice deficient in p110{gamma} (8) and p110{delta} (9) were three or six generations backcrossed to B6, respectively. To provide p110{gamma}–/– or p110{delta}D910A/D910A cells for homing and migration assays, lethally irradiated B6-Ly5.2 mice were reconstituted as described (10) with p110{gamma}–/–, p110{delta}D910A/D910A, or littermate control (+/+ or +/–) bone marrow.

Adoptive transfer assays

Donor splenocytes were prepared at 106/ml (10). For WMN experiments followed by histological examinations, B6 or IgHEL-transgenic splenocytes were labeled for 10 min at 37°C with 1.4 µM or 0.14 µM CFSE (Molecular Probes, Eugene, OR), cotreated with either 200 nM WMN (Sigma-Aldrich, St. Louis, MO) or carrier, and washed three times in RPMI 1640 plus 10% FBS. Carrier- and WMN-treated cells were transferred alone (3 x 107) or after mixing (4 x 107), and injected i.v. into Igha B6 recipients. Spleens were harvested and analyzed as described (10). For WMN treatment experiments followed by flow cytometry, CXCR5–/– or wild-type splenocytes were treated for 30 min at 37°C with 200 nM WMN or carrier, and labeled at the same time with either 1 µM CFSE or 10 µM CellTracker Orange 5- (and 6-)-(((4-chloromethyl)benzoyl)amino)tetramethylrhodamine (CMTMR) (Molecular Probes), washed, and mixed at a 1:1 ratio, and 3 x 107 cells were transferred. Splenocytes from p110{delta}D910A/D910A, p110{gamma}–/–, or littermate control chimeras labeled with 1.4 µM CFSE and from IgHEL-transgenic mice labeled with 0.14 µM CFSE were mixed at a 3:1 ratio and 4 x 107 total cells were transferred as above. The absolute frequency of p110 knockout or wild-type B cells to cotransferred control B cells in any given tissue was determined by dividing the absolute number of recovered cells by the absolute number of cotransferred IgHEL control cells. Blood sample numbers are based on a total volume of 2 ml of blood per mouse. The frequency was corrected for differences in the input ratio of p110 knockout or wild-type cells and IgHEL control cells, and transfer data were plotted as the number of cells of each type recovered in each recipient per 106 transferred cells as described (11). The absolute number of WMN-treated vs carrier-treated CXCR5–/– or CXCR5+/+ B cells were determined as for the p110 transfer experiments, except that numbers were not normalized to a cotransferred control cell population because carrier- or WMN-treated cells were cotransferred into the same recipient mouse. All statistical analyses were conducted using a two-tailed, two sample, unequal variance (unpaired) Student’s t test.

Chemotaxis, flow cytometry, and immunohistochemistry

Chemotaxis assays were with splenocytes as described (10) using uncoated 5-µm transwell filters (Corning Costar, Acton, MA) and chemokines from R&D Systems (Minneapolis, MN). In some experiments, cells were pretreated for 10 min with the indicated concentrations of WMN, with 5 µM LY294002 (Calbiochem, San Diego, CA) or carrier before the assay. Flow cytometry for chemokine receptors and immunohistochemical analysis was as described (10, 12). Cell enumeration was performed by locating well-defined mucosal addressin cell adhesion molecule-1-stained (BD Pharmingen, San Diego, CA) white pulp cords from serial sections costained with either IgMb and IgDb or hen egg lysozyme (HEL) to detect transferred B6 B cells or IgHEL-transgenic (transgenic for IgM and IgD with Igha) B cells, respectively. Cotransferred B cells were enumerated within three serial white pulp cord sections per mouse.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
PI3K dependence of lymphocyte chemotaxis to lymphoid chemokines

To examine the PI3K dependence of naive lymphocyte responses to lymphoid chemokines, spleen cells were incubated with 100 nM WMN and subjected to transwell chemotaxis assays. B cell responses to each of the lymphoid chemokines were inhibited between 65 and 85% by WMN treatment, with the inhibitory effect being most prominent at the lower chemokine doses (Fig. 1). By contrast, T cell responses were more resistant to the inhibitor, especially the responses to the efficacious T cell attractant, CCL21, where the maximal inhibitory effect was 35–65% for CD4 cells (Fig. 1). Increasing the WMN concentration to 250 nM led to only a slight increase in inhibition, and there was no further increase when 500 or 1000 nM concentrations were used (data not shown). Similar findings were obtained using a second PI3K inhibitor, LY294002 (data not shown). As expected from its covalent mechanism of action, WMN inhibitory effects were still evident at ~75% of the initial level 6 h after the inhibitor had been removed from the cultures (data not shown). These findings extend previous studies showing that lymphocyte responses to CCL5 (RANTES) and CXCL12 can be reduced or inhibited by WMN treatment (reviewed in Ref. 2), and they indicate that different lymphoid chemokine receptors have differing dependence on PI3K for mediating chemotactic responses. The basis for the incomplete block in migration is unclear, but may indicate the involvement of PI3K-independent pathways of chemotaxis in lymphocytes (1, 2, 4).



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  		FIGURE 1. Effect of WMN treatment on B and T cell chemotactic responses to lymphoid chemokines. The panels show percentage of input cells that migrated in response to the indicated concentration of chemokine in the presence (WMN, ) or absence (control, {square}) of 100 nM WMN. Bars show average (± SD) for two to six experiments where each assay was performed in duplicate.

 
Role of p110{gamma} in T cell migration and p110{delta} in B cell migration

Although previous studies of p110{gamma}-deficient mice had not indicated a role for this PI3K isoform in lymphocyte migration, our findings above led us to test whether p110{gamma}-deficient lymphocytes showed partial defects in chemotactic responsiveness. Flow cytometric analysis revealed that chemokine receptor levels on p110{gamma}-deficient B and T cells were equivalent to wild-type controls (data not shown). However, the migration of p110{gamma}-deficient CD4 and CD8 T cells to CCL19 and CXCL12, and to low doses of CCL21, was reduced by 30–65% (Fig. 2B). By contrast, B cell migration to chemokines was not significantly affected by p110{gamma} deficiency (Fig. 2B).



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  		FIGURE 2. Chemokine receptor expression and chemotactic responses of B and T lymphocytes deficient in the p110{gamma} or p110{delta} catalytic subunit of PI3K. A, Flow cytometric analysis of chemokine receptor levels on B220+ B cells deficient in p110{delta} (ko, thick black line) and wild-type cells (wt, thin black line). Staining control is indicated in a thin gray line. B and C, Chemotaxis of B lymphocytes (B220+), CD4+ or CD8+ T cells deficient (ko, ) from p110{gamma} (B) or p110{delta} (C) deficient mice compared with cells from littermate controls (wt, {square}). The percentage of the input cell population that responded to the chemokine indicated is shown. Bars indicate average (± SD) for a minimum of three to six mice per group. *, p < 0.05; **, p < 0.01; ***, p < 0.005; ****, p < 0.0005 in Student’s t test.

 
As B cell chemotactic responses were equally or more sensitive than T cell responses to the effects of WMN (Fig. 1), we explored the possibility that p110{delta}, a major PI3K isoform in lymphocytes (5, 6), was involved in B cell chemotaxis. PI3K p110{delta}-deficient B cells had normal amounts of CCR7 and CXCR5 but exhibited slightly elevated CXCR4 levels (Fig. 2A). Elevated CXCR4 levels were also seen in B cells following WMN treatment (data not shown). CCR7 and CXCR4 levels on p110{delta}-deficient T cells were equivalent to the wild-type controls. Strikingly, p110{delta}-deficient B cells showed a defect in B cell chemotaxis to all concentrations of CXCL13 (Fig. 2C). Responses to the CCR7 and CXCR4 ligands were less affected, but slight reductions in migration were detected at the lower CCL19 and CXCL12 concentrations (Fig. 2C). T cell responses were unaffected by p110{delta} deficiency, with the exception that responses to low doses of CXCL12 were reduced (Fig. 2C).

The ability of p110{delta} to function downstream of chemokine receptors in lymphocyte chemotactic responses is consistent with the finding that dominant-negative p85 reduces chemotaxis to CXCL12 (13, 14). Recently, a small molecule inhibitor of p110{delta} was identified and shown to reduce neutrophil chemotaxis to fMLP in under agarose assays, with ICAM1 as an adhesive substrate (15). The mechanism of p110{delta} coupling to chemokine receptors is unclear, but because tyrosine kinases can be activated by chemoattractant receptors, the conventional pathway of class IA PI3K activation may be involved (4). Consistent with this scenario, microinjection of p110{delta} neutralizing Abs inhibited tyrosine-kinase receptor-mediated migratory responses of a macrophage cell line to CSF-1 (16).

Requirement of p110{delta} for B cell homing

To explore the role of PI3K in B cell homing in vivo, we transferred wild-type B cells that had been treated in vitro with WMN, or cells from p110{gamma}- or p110{delta}-deficient mice, into wild-type recipients for 1.5 h. These experiments revealed reduced homing to PP of both WMN-treated and p110{delta}-deficient B cells, but normal homing of p110{gamma}-deficient B cells (Fig. 3A). p110{delta} deficiency also caused a reduction in homing to mesenteric lymph node (LN), although this effect was weaker than the effect in PP and it was not evident with WMN-treated cells. Entry into peripheral LN and to the spleen was not reduced by WMN treatment or by p110{delta} or p110{gamma} deficiency (Fig. 3A). Analysis of lymphoid organs in p110{delta}-deficient mice revealed that B cell numbers were severely diminished in PP (1.55 ± 1.2 x 106, n = 4, in wild-type vs 0.07 ± 0.01 x 106, n = 5, in p110{delta}-deficient) whereas numbers in LNs and spleen were not significantly reduced. This finding is consistent with p110{delta} playing a nonredundant role in B cell accumulation in PP.



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  		FIGURE 3. Defective homing of p110{delta}-deficient or WMN-treated B cells to PPs. A, CFSE-labeled (1.4 µM) Ighb splenocytes from p110{delta}D910A/D910A (p110{delta}–/–), p110{delta}+/+, p110{gamma}–/–, or p110{gamma}+/– chimeras were cotransferred with CFSE-labeled (0.14 µM) IgHEL-transgenic B cells into Igha congenic mice; or CFSE- or CMTMR-labeled splenocytes treated in vitro before transfer with WMN (W) were cotransferred respectively with CMTMR- or CFSE-labeled carrier-treated (C) splenocytes into recipient mice. After 1.5 h, blood and lymphoid tissues were examined for the frequency of transferred cells as described in Materials and Methods. Spleen numbers correspond to half of the spleen. B, Transfer experiments were performed as in A for the WMN- and carrier-treated group, except that CXCR5–/– and CXCR5+/+ donor cells were used. Absolute numbers of recovered WMN- (W) or carrier-treated (C) B cells in blood and secondary lymphoid tissues are shown. The average (± SD) for 5–11 recipients per group is shown. The data are representative of two to four experiments using chimeras made from at least two different knockout and wild-type bone marrows. mLN, mesenteric LN; ingLN, inginual LN. *, p < 0.005; **, p < 0.0005 in Student’s t test.

 
As p110{delta} deficiency strongly affected CXCL13 responses in vitro, and other studies have shown that entry to PP but not peripheral LN depends partially on CXCR5 (11), we tested whether the PI3K requirement for B cell entry to PP was due to PI3K acting downstream of CXCR5. For these experiments, cells from wild-type or CXCR5-deficient mice were treated with WMN or with the carrier, and then transferred to wild-type recipients. Analysis 1.5 h later revealed that homing of CXCR5-deficient B cells to PP was reduced ~65% (Fig. 3B) as expected (11). However, WMN treatment did not cause a further reduction in the PP homing of the CXCR5-deficient cells, in contrast to its inhibitory effect on the homing of wild-type cells (Fig. 3B). Therefore, we conclude that p110{delta} has a selective role in B cell entry to PP via CXCL13+ high endothelial venules (HEV). Although WMN treatment was not found to affect lymphocyte attachment to PP HEV in a previous study (17), it was not indicated whether T or B lymphocytes were being analyzed and it seems possible that the HEV under investigation were the larger CXCL13-negative vessels present in the T zone. Alternatively, the role of p110{delta} may be restricted to a CXCL13-dependent step downstream of attachment but required for B cell accumulation within the organ.

When the distribution of WMN-treated B cells within the spleen was examined 1.5 h after transfer, a strong reduction was observed in B cell entry to splenic white pulp cords (Fig. 4, A (upper panels) and B). Reduced white pulp entry was also observed for p110{delta}-deficient cells, whereas p110{gamma} deficiency had no effect on entry (Fig. 4B). B cell entry into the splenic white pulp cords depends on CXCR5, and to a lesser degree on CCR7 (18) and on the integrins {alpha}L{beta}2 and {alpha}4{beta}1 (12). Therefore, the PI3K requirement during B cell entry to white pulp cords may reflect the role of p110{delta} in CXCR5-mediated chemotaxis or possibly a role in CXCR5-mediated integrin activation.



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  		FIGURE 4. PI3K functions in B cell entry and localization in splenic white pulp cords. A, Effect of WMN pretreatment on B cell distribution in the spleen. Upper panels, Adjacent spleen sections of Igha B6 mice that had received a mixture of WMN-treated IgHEL-transgenic B cells (WMN) and carrier-treated Ighb B cells (control) 1.5 h before. Transferred IgHEL B cells were detected by staining with HEL (red, upper right panel) and transferred Ighb B cells were stained for IgMb plus IgDb (red, upper left panel). Original magnification, x10. Lower panels, Distribution of IgHEL-transgenic B cells preincubated with carrier (control) or WMN at 6 h after transfer to B6 recipient mice. Spleen sections were stained with HEL (blue) to detect IgHEL transgenic B cells. B cell follicles (B220+) are stained brown. Original magnification, x5. B, Enumeration of transferred p110{delta}-, p110{gamma}-deficient, or 200 nM WMN-treated B cell numbers in splenic white pulp cords compared with littermate control or carrier-treated B cells (C) 1.5 h after transfer. For WMN-treated cells, in half the transfers the WMN-treated cells were the IgHEL-transgenic cells, and in half they were the nontransgenic Ighb cells. Transfers were normalized to total numbers of input cells as described in Materials and Methods. Bars show average (± SD) for two to four experiments with five to seven recipient mice per group. *, p < 0.005; **, p < 0.00005 in Student’s t test.

 
We also examined whether PI3K function was important for B cell localization within the splenic white pulp by analyzing sections from mice 6 h after transfer of WMN-treated cells. By this time point, many WMN-treated B cells had entered the white pulp. However, these cells were largely excluded from lymphoid follicles and instead accumulated at the boundary of the B and T zones (Fig. 4A, lower panels). This might be explained by the greater sensitivity of CXCR5 to inhibition by WMN treatment compared with CCR7 (Fig. 1), because slight reductions in CXCR5 expression have been found to shift the balance of chemokine responsiveness sufficiently to promote B cell positioning in this location (7, 10).

In summary, we establish differential roles for p110{gamma} and p110{delta} in T and B cell chemotaxis, demonstrating a particularly prominent role for p110{delta} in B cell responses to CXCL13. Differential PI3K usage by different chemokine receptors and different cell types is likely to be important in allowing cells to appropriately interpret complex chemokine environments, such as those that exist within lymphoid organs.


   Acknowledgments
 
We thank Martin Lipp for CXCR5-deficient mice, Caroline Low and Ying Xu for assistance with the mouse colony, Matt Lesneski for help with chemotaxis assays, and Takaharu Okada for comments on the manuscript.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by the Leukemia and Lymphoma Society (to K.R.), the Howard Hughes Medical Institute (to J.G.C.), and National Institutes of Health Grant AI-40098 (to J.G.C.). Research in the laboratory of B.V. is funded by the Ludwig Institute for Cancer Research, the Biotechnology and Biological Science Research Council, and the European Union Fifth Framework Programme QLG1-2001-02171. Back

2 Current address: Department of Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. Back

3 Address correspondence and reprint requests to Dr. Jason G. Cyster, Department of Microbiology and Immunology, University of California, 513 Parnassus Ave., San Francisco, CA 94143. E-mail address: cyster{at}itsa.ucsf.edu Back

4 Abbreviations used in this paper: WMN, wortmannin; LN, lymph node; PP, Peyer’s patch; HEL, hen egg lysozyme; HEV, high endothelial venule; CMTMR, 5- (and 6-)-(((4-chloromethyl)benzoyl)amino)tetramethylrhodamine. Back

Received for publication April 20, 2004. Accepted for publication June 18, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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