IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy.
Interleukin-2 (IL-2) is a lymphocyte growth factor that is an important component of many immune-based cancer therapies. The efficacy of IL-2 is thought to be limited by the expansion of T regulatory cells, which express the high-affinity IL-2 receptor subunit IL-2Rα. IL-15 is under investigation as an alternative to IL-2. Although both cytokines signal through IL-2Rβγ, IL-15 does not bind IL-2Rα and therefore induces less T regulatory cell expansion. However, we found that transferred effector CD8(+) T cells induced curative responses in lymphoreplete mice only with IL-2-based therapy. Although conventional in vitro assays showed similar effector T cell responsiveness to IL-2 and IL-15, upon removal of free cytokine, IL-2 mediated sustained signaling dependent on IL-2Rα. Mechanistically, IL-2Rα sustained signaling by promoting a cell surface IL-2 reservoir and recycling of IL-2 back to the cell surface. Our results demonstrate that IL-2Rα endows T cells with the ability to compete temporally for limited IL-2 via mechanisms beyond ligand affinity. These results suggest that strategies to enhance IL-2Rα expression on tumor-reactive lymphocytes may facilitate the development of more effective IL-2-based therapies.
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Ee W
EW
Su
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Caitlin J
CJ
Moore
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Samantha
S
Suriano
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Christopher Bryce
CB
Johnson
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Neizel
N
Songalia
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Alicia
A
Patterson
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Daniel J
DJ
Neitzke
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Kristina
K
Andrijauskaite
Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Elizabeth
E
Garrett-Mayer
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Shikhar
S
Mehrotra
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
Chrystal M
CM
Paulos
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Andrew L
AL
Doedens
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Ananda W
AW
Goldrath
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
Zihai
Z
Li
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
David J
DJ
Cole
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA. markrubinstein@musc.edu.
Mark P
MP
Rubinstein
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D007167:Immunotherapy / Q000379:methods*; D019409:Interleukin-15 / Q000627:therapeutic use; D007376:Interleukin-2 / Q000276:immunology* / Q000627:therapeutic use; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D015398:Signal Transduction / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D019409:Interleukin-15; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit