IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy

IL-2Rα mediated signalling defines the candidacy of IL-2

Interleukin-2 is a member of IL-2 family cytokine consisting of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, mediates differentiation of primary T cells into T-reg, T-cytotoxic and T-helper cells. It also has regulation on key immune functions like development of immunogenic memory in T cells, development of immune tolerance and clearance of cancer cells. The expression and signalling of IL-2 is tightly regulated in both negative and positive feedback loop. IL-2R, the receptor for IL-2 is expressed on leukocyte and lymphocytes cell surface is a complex of α, β and ϒ chains, where α-subunit has lower affinity for its ligand can increases upto 100 folds when complexed to β and ϒ chains (1). The commercial use of IL-2 as a chemotherapeutic drug is FDA approved in cancer therapy, but due to short life span and requirement of high therapeutic dose, it exhibits cytotoxic effects on host immune system. The cytokines IL-2 mediates its signalling cascade biased through IL2Rα constitutively expressed on T-reg cells that’s why IL-2 is the most essential for survival and expansion of T-reg cells. Su et al (2) investigated that administration of IL-2/m-Ab-IL-2 complex with increased half life demonstrates stronger and persistent effector T- cells function of transferred tumor reactive T cells in B6 model cancer mice. Authors have demonstrated that expression of IL-2Rα on donor cells outcompetes to the existing host cells for limited availability of IL-2, that provide a competitive advantage of IL-2 therapy into lymphoreplate host environment over lymphodeplete one. During IL-2 signalling, unlike IL-2Rβϒ, IL-2Rα subunit is recycled back, that directs a sustained cytokine signalling cascade even after withdrawal of IL-2 cytokines (2). The enhanced and sustained signalling is mediated through IL2-Rα controlled creation of extra cellular reservoir and recycling of IL-2 back to cell surface. Ahead of cancer TB is more prevalent in countries like India and China. During infection of Mycobacterium tuberculosis (MTB) and treatment administration the dynamic ratio of IFNG/IL-2 play a crucial role in regulation and clearance of pathogenic load (3), where IL-2 can be explored in therapeutic regime? According to Su et al IL-2 therapy can be of high value for non lymphopenic patients when responding T cells expresser higher level of IL-2Rα. These findings suggest that IL-2 is a key regulator of immune functions and its fine tuning can be modulated for immunothrepies of cancer and other infectious disease, where benefits for TB patients is warned through further research.

References

1. S. L. Gaffen, K. D. Liu, Overview of interleukin-2 function, production and clinical applications. Cytokine. 28, 109–123 (2004).
2. E. W. Su, C. J. Moore, S. Suriano, C. B. Johnson, N. Songalia, A. Patterson, D. J. Neitzke, K. Andrijauskaite, E. Garrett-Mayer, S. Mehrotra, C. M. Paulos, A. L. Doedens, A. W. Goldrath , Z. Li, D. J. Cole, M. P. Rubinstein, IL-2Ra mediates temporal regulation of IL-2 signaling and enhances immunotherapy. Sci. Transl. Med. 7, 311ra170 (2015).
3. F. Suter-Riniker, A. Berger, D. Mayor, P. Bittel, P. Iseli, T. Bodmer, Clinical Significance of Interleukin-2/Gamma Interferon Ratios in Mycobacterium tuberculosis-Specific T-Cell Signature. Clin Vaccine Immunol 18, 1395–1396 (2011).