Global transcriptional analysis delineates the differential inflammatory response interleukin-15 elicits from cultured human T cells.
OBJECTIVE
Interleukin 15 (IL)-15 controls proliferation and survival of T cells, but its effects and the underlying cellular regulation are not well understood. Previous studies have focused on its effects on short-term T-cell cultures. In view of the potential problems associated with using IL-2 alone in adoptive immunotherapy protocols, we investigated the impact of IL-15 on T-cell cultures and the global transcriptional effects it elicits in such cultures.


METHODS
DNA microarrays and flow cytometry were used to examine the differential effect of 20 ng/mL IL-15 on primary serum-free T-cell cultures activated and cultured in the presence of IL-2. Quantitative reverse transcriptase polymerase chain reaction confirmed select microarray data.


RESULTS
IL-15 significantly increased ex vivo expansion of primary human T cells over the entire 11-day expansions without affecting viability. The 1133 genes were consistently differentially expressed among three donor samples. Ontological analysis demonstrated that IL-15 increases expression of genes involved in inflammatory response (e.g., tumor necrosis factor [TNF]-alpha, Oncostatin M, CD40L, and CD33) and apoptosis (e.g., TNF-related apoptosis-inducing ligand). IL-15 also induced expression of four suppressors of cytokine signaling (SOCS) family genes (SOCS1-3, cytokine-inducible SH2-containing protein), which are classical negative regulators of cytokine signaling. IL-15 strongly suppressed the expression of inhibitory natural killer cell receptor genes, including three C-type lectins (KLRB1, KLRC1, and KLRD1), as well as IL-7Ra and Granzyme H. Finally, IL-15 induced differential expression of TNF receptor superfamily members (CD27 and CD30).


CONCLUSIONS
These findings suggest that exogenous IL-15 may have a potential role in adoptive immunotherapy by both enhancing proliferation and modulating functionality during ex vivo T-cell expansion.
Ramsborg
Christopher G
CG
Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208-3120, USA.
Papoutsakis
E Terry
ET
D015703:Antigens, CD / Q000187:drug effects / Q000235:genetics; D017209:Apoptosis / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016000:Cluster Analysis; D005434:Flow Cytometry / Q000379:methods; D020869:Gene Expression Profiling; D053804:Granzymes / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D019409:Interleukin-15 / Q000276:immunology* / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D011971:Receptors, Immunologic / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D050826:Suppressor of Cytokine Signaling Proteins / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D014158:Transcription, Genetic
D015703:Antigens, CD; D019409:Interleukin-15; D007376:Interleukin-2; D011971:Receptors, Immunologic; D050826:Suppressor of Cytokine Signaling Proteins; C069434:GZMH protein, human; D053804:Granzymes