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Cell Subsets NKT Βα Homing Patterns of Murine TCR Differential Differential Chemokine Responses and Homing Patterns of Murine TCR αβ NKT Cell Subsets This information is current as Brent Johnston, Chang H. Kim, Dulce Soler, Masashi Emoto of October 3, 2021. and Eugene C. Butcher J Immunol 2003; 171:2960-2969; ; doi: 10.4049/jimmunol.171.6.2960 http://www.jimmunol.org/content/171/6/2960 Downloaded from References This article cites 66 articles, 37 of which you can access for free at: http://www.jimmunol.org/content/171/6/2960.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 October 3, 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 © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Differential Chemokine Responses and Homing Patterns of Murine TCR␣␤ NKT Cell Subsets1 Brent Johnston,2* Chang H. Kim,3* Dulce Soler,† Masashi Emoto,‡ and Eugene C. Butcher* NKT cells play important roles in the regulation of diverse immune responses. Therefore, chemokine receptor expression and chemotactic responses of murine TCR␣␤ NKT cells were examined to define their homing potential. Most NKT cells stained for the chemokine receptor CXCR3, while >90% of V␣14i-positive and ϳ50% of V␣14i-negative NKT cells expressed CXCR6 via an enhanced green fluorescent protein reporter construct. CXCR4 expression was higher on V␣14i-negative than V␣14i-positive NKT cells. In spleen only, subsets of V␣14i-positive and -negative NKT cells also expressed CXCR5. NKT cell subsets migrated in response to ligands for the inflammatory chemokine receptors CXCR3 (monokine induced by IFN-␥/CXC ligand (CXCL)9) and CXCR6 (CXCL16), and regulatory chemokine receptors CCR7 (secondary lymphoid-tissue chemokine (SLC)/CC ligand (CCL)21), CXCR4 (stromal cell-derived factor-1/CXCL12), and CXCR5 (B cell-attracting chemokine-1/CXCL13); but not to ligands for other chemokine receptors. Two NKT cell subsets migrated in response to the lymphoid homing chemokine SLC/ Downloaded from CCL21: CD4؊ V␣14i-negative NKT cells that were L-selectinhigh and enriched for expression of Ly49G2 (consistent with the phenotype of most NKT cells found in peripheral lymph nodes); and immature V␣14i-positive cells lacking NK1.1 and L-selectin. Mature NK1.1؉ V␣14i-positive NKT cells did not migrate to SLC/CCL21. BCA-1/CXCL13, which mediates homing to B cell zones, elicited migration of V␣14i-positive and -negative NKT cells in the spleen. These cells were primarily CD4؉ or CD4؊CD8؊ and were enriched for Ly49C/I, but not Ly49G2. Low levels of chemotaxis to CXCL16 were only detected in V␣14i-positive NKT cell subsets. Our results identify subsets of NKT cells with distinct homing and localization patterns, suggesting that these http://www.jimmunol.org/ populations play specialized roles in immunological processes in vivo. The Journal of Immunology, 2003, 171: 2960–2969. atural killer T cells constitute a lineage of hemopoietic MHCs, and can be identified using CD1d tetramers loaded with cells that share both phenotypic and functional charac- ␣-galactosylceramide (␣-GalCer) (3, 4). Interestingly, an imma- N teristics with NK cells and effector T lymphocytes. ture subset of V␣14i NKT cells lacks expression of NK1.1 and Mouse NKT cells are often defined by their expression of TCR and constitutes the major population of NKT cells proliferating in the ␣ NK markers such as NK1.1 (CD161), DX5 ( 2 integrin), CD122, thymus of mice (5, 6). These cells are exported from the thymus or Ly49 family members (reviewed in Refs. 1 and 2). Many NKT and subsequently acquire NK1.1 expression in peripheral tissues by guest on October 3, 2021 cells express a highly restricted TCR repertoire consisting of an (5, 6), suggesting that NK1.1 up-regulation is associated with a invariant TCR␣ chain, V␣14J␣18, paired preferentially with the thymus-independent NKT cell maturation step. Most cells in the TCR␤ chains V␤8.2, V␤7, or V␤2. These invariant NKT cells, tetramer-negative population have diverse TCR usage and are not recently designated V␣14i T cells, recognize glycolipids associ- CD1d-restricted. However, this population also includes small ␤ ␤ 4 ␣ ated with CD1d and 2-microglobulin ( 2m) rather than classical subsets of CD1d-restricted NKT cells that do not recognize -Gal- Cer (2, 7). NKT cells have been shown to play important roles in diverse *Laboratory of Immunology and Vascular Biology, Department of Pathology, Stan- immune responses including the control of microbial infections, ford University School of Medicine, Stanford, CA 94305, and Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA tumor killing, tolerance induction, and suppression of autoim- 94304; †Millennium Pharmaceuticals, Cambridge, MA 02142; and ‡Department of munity (reviewed in Refs. 1, 2, 8 and 9). In vivo, NKT cells are Immunology, Max Planck Institute for Infection Biology, Berlin, Germany infrequent in the blood and lymph nodes, but accumulate at Received for publication January 29, 2003. Accepted for publication July 16, 2003. higher levels in the liver, bone marrow, and spleen. After in- The costs of publication of this article were defrayed in part by the payment of page oculation with mycobacterial glycolipids, or infection with charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. other microbial agents, NKT cells have been found to accumu- 1 This work was supported by grants from the National Institutes of Health and the late in affected tissues (10–14). Similarly, NKT cells accumu- Department of Veterans Affairs (to E.C.B.), and the FACS Core Facility of the Stan- late in the spleen during tolerance induction to Ags introduced ford Digestive Diseases Center. B.J. was supported by a fellowship from the Canadian via the ocular route (15), and bone marrow NKT cells repopu- Institutes of Health Research. late the liver after depletion with low dose anti-CD3 Ab treat- 2 Address correspondence and reprint requests to Dr. Brent Johnston, Veterans Affairs Medical Center, 3801 Miranda Avenue, MC154B, Palo Alto, CA 94304. E-mail ad- ment (16). However, little is known about the homing mecha- dress: [email protected] nisms that NKT cells use to reglate their distribution in the 3 Current address: Department of Pathobiology, Purdue University, 1243 Veterinary periphery, or migrate to inflamed tissues. Pathology Building, West Lafayette, IN 47907-1243. Chemokines mediate leukocyte adhesion and migration, al- 4 ␤ ␤ ␣ ␣ Abbreviations used in this paper: 2m, 2-microglobulin; GalCer, -galactosyl- lowing the homing of specific leukocyte subsets to normal and ceramide; SLC, secondary lymphoid-tissue chemokine; CCL, CC ligand; BCA, B inflamed tissue sites based on differential expression of chemo- cell-attracting chemokine; CXCL, CXC ligand; GFP, green fluorescent protein; eGFP, enhanced GFP; MIP, macrophage inflammatory protein; MDC, monocyte-derived kines and their receptors (reviewed in Refs. 17 and 18). The chemokine; MIG, monokine induced by IFN-␥; IP-10, IFN-␥-inducible protein-10; chemokine secondary lymphoid-tissue chemokine (SLC)/CC li- SDF, stromal cell-derived factor; TCA, T cell activation protein; TECK, thymus- expressed chemokine; CTACK, cutaneous T cell-attracting chemokine; XCL, XC gand (CCL)21 and its receptor, CCR7, regulate the basal hom- ligand; DN, double-negative. ing of T lymphocytes into lymph nodes, while B cell attracting Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 The Journal of Immunology 2961 chemokine (BCA)-1/CXC ligand (CXCL)13 mediates the local- tom wells (checkerboard analysis) to distinguish chemotaxis from ization of B lymphocytes and specialized T lymphocyte subsets chemokinesis. to follicular areas of the lymph node. Differential chemokine Flow cytometry receptor expression on memory/effector lymphocyte subsets al- lows for their recruitment into specific tissue sites. For example, The following conjugated mAbs were used in various staining protocols: FITC, PE, or allophycocyanin-labeled NK1.1 (clone PK136); FITC, PE, or skin homing lymphocytes express CCR4, while CCR9 is pref- CyChrome-labeled TCR␤ (clone H57-597); FITC, PE, PerCP, or allophy- erentially expressed on lymphocytes that home to intestinal tis- cocyanin-labeled CD4 (clone RM4-5); allophycocyanin-CD8␣ (clone 53- sues. To investigate whether NKT cell homing and tissue seg- 6.7); PE-CD19 (clone 1D3); allophycocyanin-CD11b (clone M1/70); allo- regation could be regulated by chemokine receptor expression phycocyanin-L-selectin (clone Mel-14); allophycocyanin-Ly49G2 (clone and chemokine responsiveness, we examined the chemotactic 4D11); PE-Ly49C/I (clone SW5E6); biotin-CXCR4 (clone 2B11/CXCR4); ␣␤ and biotin-CXCR5 (clone 2G8) were all from BD PharMingen (San Diego, responses of
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