CD26 is a leukocyte activation marker that possesses dipeptidyl peptidase IV activity but whose natural substrates and immunological functions have not been clearly defined. Several chemo-kines, including RANTES (regulated on activation, normal T cell expressed and secreted), have now been shown to be substrates for recombinant soluble human CD26. The truncated RANTES(3–68) lacked the ability of native RANTES(1–68) to increase the cytosolic calcium concentration in human monocytes, but still induced this response in macrophages activated with macrophage colony-stimulating factor. Analysis of chemokine receptor messenger RNAs and patterns of desensitization of chemokine responses showed that the differential activity of the truncated molecule results from an altered receptor specificity. RANTES(3–68) showed a reduced activity, relative to that of RANTES(1–68), with cells expressing the recombinant CCR1 chemokine receptor, but retained the ability to stimulate CCR5 receptors and to inhibit the cytopathic effects of HIV-1. Our results indicate that CD26-mediated processing together with cell activation–induced changes in receptor expression provides an integrated mechanism for differential cell recruitment and for the regulation of target cell specificity of RANTES, and possibly other chemokines.
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1 December 1997
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December 01 1997
Regulation of the Receptor Specificity and Function of the Chemokine RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted) by Dipeptidyl Peptidase IV (CD26)-mediated Cleavage
Tamas Oravecz,
Tamas Oravecz
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
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Marina Pall,
Marina Pall
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
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Gregory Roderiquez,
Gregory Roderiquez
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
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Mark D. Gorrell,
Mark D. Gorrell
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
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Mary Ditto,
Mary Ditto
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
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Nga Y. Nguyen,
Nga Y. Nguyen
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
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Robert Boykins,
Robert Boykins
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
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Edward Unsworth,
Edward Unsworth
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
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Michael A. Norcross
Michael A. Norcross
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
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Tamas Oravecz
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
Marina Pall
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
Gregory Roderiquez
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
Mark D. Gorrell
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
Mary Ditto
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
Nga Y. Nguyen
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
Robert Boykins
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
Edward Unsworth
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
Michael A. Norcross
From the *Division of Hematologic Products, ‡Division of Allergenics Products and Parasitology, and §Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892; and ‖A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales 2042, Australia
Address correspondence to Michael A. Norcross or Tamas Oravecz, Division of Hematologic Products, Center for Biologics Evaluation and Research, FDA, NIH, Bldg 29B, Rm 4E12, HFM-541, Bethesda, MD 20892. Phone: 301-827-0793; FAX: 301-480-3256; E-mail: [email protected] or [email protected]
Note added in proof. We note that a CD8+ T cell–derived HIV-1 suppressor activity has been recently identified as a truncated form of macrophage-derived chemokine (MDC), missing a glycine–proline dipeptide from the NH2 terminus (Pal, R., A. Garzino-Demo, P.D. Markham, J. Burns, M. Brown, R.C. Gallo, and A.L. DeVico. 1997. Science. 278:695–698). Based on our results, we suggest that truncation of MDC is a consequence of CD26-mediated cleavage that may have resulted in enhanced MDC antiviral activity.
1
Abbreviations used in this paper: [Ca2+]i, cytosolic free Ca2+ concentration; DPPIV, dipeptidyl peptidase IV; E+, enzymatically active; E−, enzymatically deficient; ES-MS, electrospray mass spectrometry; GAPDH, glyceraldehyde phosphate dehydrogenase; HEK, human embryonic kidney; HOS, human osteosarcoma; IP, interferon-γ-inducible protein; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; pNA, p-nitroanilide; RANTES, regulated on activation, normal T cell expressed and secreted; rh, recombinant human; s, soluble; SDF, stromal-derived factor.
Received:
June 04 1997
Revision Received:
September 22 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1997
J Exp Med (1997) 186 (11): 1865–1872.
Article history
Received:
June 04 1997
Revision Received:
September 22 1997
Citation
Tamas Oravecz, Marina Pall, Gregory Roderiquez, Mark D. Gorrell, Mary Ditto, Nga Y. Nguyen, Robert Boykins, Edward Unsworth, Michael A. Norcross; Regulation of the Receptor Specificity and Function of the Chemokine RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted) by Dipeptidyl Peptidase IV (CD26)-mediated Cleavage . J Exp Med 1 December 1997; 186 (11): 1865–1872. doi: https://doi.org/10.1084/jem.186.11.1865
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