Propagation and Control of T Cell Responses by Heparan Sulfate-Bound IL-21

IL-2, a cytokine produced by T cells, is a key regulator of immune responses and T cell homeostasis. Controlling the availability of IL-2 is consequently of significant import to the immune system. Like other cytokines, IL-2 is thought to function as a soluble agonist, transiently present when secreted in response to appropriate stimuli. In this study, we show that the most salient properties of IL-2, propagation and control of T cell responses, are mediated in vivo by bound and not free cytokine and specifically by heparan sulfate-bound IL-2. These findings necessitate a new look at how IL-2 regulates immune responses and support the notion that the microenvironment plays a determining role in modulating the character of immune responses.

[1]  Z. Shriver,et al.  Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[2]  K. Fukushima,et al.  Carbohydrate Recognition Site of Interleukin-2 in Relation to Cell Proliferation* , 2001, The Journal of Biological Chemistry.

[3]  E. Nabel,et al.  Extracellular matrix interacts with soluble CD95L: Retention and enhancement of cytotoxicity , 2001, Nature Immunology.

[4]  L. Lefrançois,et al.  Preferential Localization of Effector Memory Cells in Nonlymphoid Tissue , 2001, Science.

[5]  A. Khoruts,et al.  Visualizing the generation of memory CD4 T cells in the whole body , 2001, Nature.

[6]  D. Schuppan,et al.  Collagens Serve as an Extracellular Store of Bioactive Interleukin 2* , 2000, The Journal of Biological Chemistry.

[7]  J. Todd,et al.  Differential glycosylation of interleukin 2, the molecular basis for the NOD Idd3 type 1 diabetes gene? , 2000, Cytokine.

[8]  J. Platt,et al.  Regulation of T cell homeostasis by heparan sulfate-bound IL-2. , 1999, Journal of immunology.

[9]  D. Baltimore,et al.  Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activation-induced cell death. , 1999, Immunity.

[10]  M. Gordon,et al.  Further characterization of the binding of human recombinant interleukin 2 to heparin and identification of putative binding sites. , 1998, Glycobiology.

[11]  A. Khoruts,et al.  A Natural Immunological Adjuvant Enhances T Cell Clonal Expansion through a CD28-dependent, Interleukin (IL)-2–independent Mechanism , 1998, The Journal of experimental medicine.

[12]  J. Russell,et al.  Partial signaling by cytokines: cytokine regulation of cell cycle and Fas-dependent, activation-induced death in CD4+ subsets. , 1997, Cellular immunology.

[13]  H. Yoshida,et al.  Structural differences and the presence of unsubstituted amino groups in heparan sulphates from different tissues and species. , 1997, The Biochemical journal.

[14]  E. Robinet,et al.  Human T cells require IL-2 but not G1/S transition to acquire susceptibility to Fas-mediated apoptosis. , 1996, Journal of immunology.

[15]  J. Platt,et al.  Shedding of heparan sulfate proteoglycan by stimulated endothelial cells: Evidence for proteolysis of cell‐surface molecules , 1996, Journal of cellular physiology.

[16]  Zining Wu,et al.  A Point Mutation in Interleukin-2 That Alters Ligand Internalization* , 1996, The Journal of Biological Chemistry.

[17]  P. Linsley,et al.  Lipopolysaccharide interferes with the induction of peripheral T cell death. , 1995, Immunity.

[18]  T. Wight,et al.  Characterization of proteoglycans synthesized by murine embryonal carcinoma cells (P19) reveals increased expression of perlecan (heparan sulfate proteoglycan) during neuronal differentiation , 1994, Journal of neuroscience research.

[19]  P. Anderson,et al.  Effects of Route and Formulation on Clinical Pharmacokinetics of Interleukin-2 , 1994, Clinical pharmacokinetics.

[20]  D. Loh,et al.  Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. , 1994, Immunity.

[21]  John I. Gallin,et al.  Inflammation: Basic Principles and Clinical Correlates , 1992 .

[22]  M. Lenardo.  lnterleukin-2 programs mouse αβ T lymphocytes for apoptosis , 1991, Nature.

[23]  A. Linker,et al.  Biological implications of the structural, antithrombin affinity and anticoagulant activity relationships among vertebrate heparins and heparan sulphates. , 1986, The Biochemical journal.

[24]  D. Cantrell,et al.  Interleukin 2 regulates its own receptors. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Favata,et al.  Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics. , 1983, Journal of immunology.

[26]  Kendall A. Smith,et al.  T cell growth factor: parameters of production and a quantitative microassay for activity. , 1978, Journal of immunology.

[27]  R. Gallo,et al.  Selective in vitro growth of T lymphocytes from normal human bone marrows. , 1976, Science.

[28]  L. Lowenstein,et al.  A Factor stimulating DNA Synthesis derived from the Medium of Leucocyte Cultures , 1965, Nature.

[29]  T. Strom,et al.  IL-15 and IL-2: a matter of life and death for T cells in vivo , 2001, Nature Medicine.