title: Increasing the biological activity of IL-2 and IL-15 through complexing with anti-IL-2 mAbs and IL-15Rα-Fc chimera.
abstract: IL-2 and IL-15 are structurally relative cytokines that share two receptor subunits, CD132 (γ(c) chain) and CD122 (β chain). However, the expression pattern and physiological role of IL-2 and IL-15 private receptor α chains CD25 and IL-15Rα, respectively, are strikingly different. CD25, together with CD122 and CD132, forms a trimeric high affinity IL-2 receptor that is expressed and functions on cells acquiring an IL-2 signal. Conversely, IL-15Rα is expressed and binds IL-15 with high affinity per se already in the endoplasmic reticulum of the IL-15 producing cells and it presents IL-15 to cells expressing CD122/CD132 dimeric receptor in trans. Thus, while IL-2 is secreted almost exclusively by activated T cells and acts as a free molecule, IL-15 is expressed mostly by myeloid cells and works as a cell surface-associated cytokine. Interestingly, the in vivo biological activity of IL-2 can be dramatically increased through complexing with certain anti-IL-2 mAbs; such IL-2/anti-IL-2 mAbs immunocomplexes selectively stimulate the proliferation of a distinct population of immune cells, depending on the clone of the anti-IL-2 mAb used. IL-2/S4B6 mAb immunocomplexes are highly stimulatory for CD122(high) populations (memory CD8(+) T and NK cells) and intermediately also for CD25(high) populations (Treg and activated T cells), while IL-2/JES6-1 mAb immunocomplexes enormously expand only CD25(high) cells. Although IL-2 immunocomplexes are much more potent than IL-2 in vivo, they show comparable to slightly lower activity in vitro. The in vivo biological activity of IL-15 can be dramatically increased through complexing with recombinant IL-15Rα-Fc chimera; however, IL-15/IL-15Rα-Fc complexes are significantly more potent than IL-15 both in vivo and in vitro. In this review we summarize and discuss the features and biological relevance of IL-2/anti-IL-2 mAbs and IL-15/IL-15Rα-Fc complexes, and try to foreshadow their potential in immunological research and immunotherapy.
authors: Laboratory of Tumor Immunology, Institute of Microbiology of Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic.
authors: Petra
authors: P
authors: Votavova
authors: Laboratory of Tumor Immunology, Institute of Microbiology of Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic.
authors: Jakub
authors: J
authors: Tomala
authors: Laboratory of Tumor Immunology, Institute of Microbiology of Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic. Electronic address: makovar@biomed.cas.cz.
authors: Marek
authors: M
authors: Kovar
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000936:Antigen-Antibody Complex / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000276:immunology; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D053720:Interleukin-15 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology*; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; C569274:IL15 protein, human; C508017:IL2RA protein, human; C507941:IL2RG protein, human; D007141:Immunoglobulin Fc Fragments; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit
keywords: Anti-IL-2 mAb; Biological activity; IL-15; IL-15Rα-Fc chimera; IL-2; Immunocomplexes