Distinct Roles for IL-2 and IL-15 in the Differentiation and Survival of CD8+ Effector and Memory T Cells

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2010 May 21

PMID 20483725

Citations 64

Authors

Diana M Mitchell

Eugene V Ravkov

Matthew A Williams

Affiliations

Soon will be listed here.

Abstract

IL-2 provides a memory differentiation signal to CD8+ T cells during the primary response that impacts the ability of the subsequent memory pool to mount a successful recall response. In this study, we find that although primary effector CTL development is modestly decreased in the absence of IL-2, the persistence of short-term and long-term effector memory CD8+ T cells on pathogen clearance is greatly diminished. Furthermore, secondary challenge of CD8+ memory T cells lacking the high-avidity IL-2R results in a failure to repopulate the effector pool. The role of IL-2 in promoting effector differentiation is not shared with the highly related cytokine, IL-15. Although IL-15 supports the survival of effector CD8+ T cells after pathogen clearance, its absence does not impair either primary or secondary effector CTL differentiation, nor does it impact the differentiation of long-term effector memory CD8+ T cells. These findings indicate a unique role for IL-2, but not IL-15, in promoting the differentiation not only of primary effector CD8+ T cells, but also of CD8+ memory T cells capable of secondary effector differentiation.

Citing Articles

Capivasertib enhances chimeric antigen receptor T cell activity in preclinical models of B cell lymphoma.

Hsieh H, Urak R, Clark M, Kwak L, Forman S, Wang X Mol Ther Methods Clin Dev. 2025; 33(1):101421.

PMID: 40008088 PMC: 11850743. DOI: 10.1016/j.omtm.2025.101421.

Outer retina micro-inflammation is driven by T cell responses prior to retinal degeneration in early age-related macular degeneration.

Sturzbecher L, Bartolomaeus H, Bartolomaeus T, Bolz S, Sekulic A, Ueffing M Front Immunol. 2025; 16:1520188.

PMID: 39975545 PMC: 11835843. DOI: 10.3389/fimmu.2025.1520188.

Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation.

Lakhani A, Chen X, Chen L, Hong M, Khericha M, Chen Y Nat Metab. 2024; 6(6):1143-1160.

PMID: 38658805 PMC: 11845092. DOI: 10.1038/s42255-024-01034-7.

OCA-B/Pou2af1 is sufficient to promote CD4 T cell memory and prospectively identifies memory precursors.

Sun W, Hughes E, Kim H, Perovanovic J, Charley K, Perkins B Proc Natl Acad Sci U S A. 2024; 121(9):e2309153121.

PMID: 38386711 PMC: 10907311. DOI: 10.1073/pnas.2309153121.

Stat5 opposes the transcription factor Tox and rewires exhausted CD8 T cells toward durable effector-like states during chronic antigen exposure.

Beltra J, Abdel-Hakeem M, Manne S, Zhang Z, Huang H, Kurachi M Immunity. 2023; 56(12):2699-2718.e11.

PMID: 38091951 PMC: 10752292. DOI: 10.1016/j.immuni.2023.11.005.

References

Shin H, Blackburn S, Intlekofer A, Kao C, Angelosanto J, Reiner S . A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity. 2009; 31(2):309-20. PMC: 2747257. DOI: 10.1016/j.immuni.2009.06.019. View

Rubinstein M, Lind N, Purton J, Filippou P, Best J, McGhee P . IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response. Blood. 2008; 112(9):3704-12. PMC: 2572798. DOI: 10.1182/blood-2008-06-160945. View

Manjunath N, Shankar P, Wan J, Weninger W, Crowley M, Hieshima K . Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. J Clin Invest. 2001; 108(6):871-8. PMC: 200936. DOI: 10.1172/JCI13296. View

Rosenberg S, Yang J, Topalian S, Schwartzentruber D, Weber J, Parkinson D . Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994; 271(12):907-13. View

Leone A, Picker L, Sodora D . IL-2, IL-7 and IL-15 as immuno-modulators during SIV/HIV vaccination and treatment. Curr HIV Res. 2009; 7(1):83-90. DOI: 10.2174/157016209787048519. View

Atkins M, Lotze M, Dutcher J, Fisher R, Weiss G, Margolin K . High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999; 17(7):2105-16. DOI: 10.1200/JCO.1999.17.7.2105. View

Pearce E, Mullen A, Martins G, Krawczyk C, Hutchins A, Zediak V . Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science. 2003; 302(5647):1041-3. DOI: 10.1126/science.1090148. View

Becker T, Wherry E, Boone D, Murali-Krishna K, Antia R, Ma A . Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J Exp Med. 2002; 195(12):1541-8. PMC: 2193552. DOI: 10.1084/jem.20020369. View

Chang J, Palanivel V, Kinjyo I, Schambach F, Intlekofer A, Banerjee A . Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science. 2007; 315(5819):1687-91. DOI: 10.1126/science.1139393. View

10.

Schluns K, Williams K, Ma A, Zheng X, Lefrancois L . Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol. 2002; 168(10):4827-31. DOI: 10.4049/jimmunol.168.10.4827. View

11.

Oh S, Berzofsky J, Burke D, Waldmann T, Perera L . Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity. Proc Natl Acad Sci U S A. 2003; 100(6):3392-7. PMC: 152303. DOI: 10.1073/pnas.0630592100. View

12.

Sarkar S, Teichgraber V, Kalia V, Polley A, Masopust D, Harrington L . Strength of stimulus and clonal competition impact the rate of memory CD8 T cell differentiation. J Immunol. 2007; 179(10):6704-14. DOI: 10.4049/jimmunol.179.10.6704. View

13.

Williams M, Ravkov E, Bevan M . Rapid culling of the CD4+ T cell repertoire in the transition from effector to memory. Immunity. 2008; 28(4):533-45. PMC: 2391296. DOI: 10.1016/j.immuni.2008.02.014. View

14.

Cruz-Guilloty F, Pipkin M, Djuretic I, Levanon D, Lotem J, Lichtenheld M . Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J Exp Med. 2009; 206(1):51-9. PMC: 2626671. DOI: 10.1084/jem.20081242. View

15.

Yajima T, Nishimura H, Wajjwalku W, Harada M, Kuwano H, Yoshikai Y . Overexpression of interleukin-15 in vivo enhances antitumor activity against MHC class I-negative and -positive malignant melanoma through augmented NK activity and cytotoxic T-cell response. Int J Cancer. 2002; 99(4):573-8. DOI: 10.1002/ijc.10395. View

16.

Wherry E, Becker T, Boone D, Kaja M, Ma A, Ahmed R . Homeostatic proliferation but not the generation of virus specific memory CD8 T cells is impaired in the absence of IL-15 or IL-15Ralpha. Adv Exp Med Biol. 2002; 512:165-75. DOI: 10.1007/978-1-4615-0757-4_22. View

17.

Whitton J, Southern P, Oldstone M . Analyses of the cytotoxic T lymphocyte responses to glycoprotein and nucleoprotein components of lymphocytic choriomeningitis virus. Virology. 1988; 162(2):321-7. DOI: 10.1016/0042-6822(88)90471-0. View

18.

Williams M, Bevan M . Shortening the infectious period does not alter expansion of CD8 T cells but diminishes their capacity to differentiate into memory cells. J Immunol. 2004; 173(11):6694-702. DOI: 10.4049/jimmunol.173.11.6694. View

19.

Kaech S, Wherry E . Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity. 2007; 27(3):393-405. PMC: 3431921. DOI: 10.1016/j.immuni.2007.08.007. View

20.

Agarwal P, Raghavan A, Nandiwada S, Curtsinger J, Bohjanen P, Mueller D . Gene regulation and chromatin remodeling by IL-12 and type I IFN in programming for CD8 T cell effector function and memory. J Immunol. 2009; 183(3):1695-704. PMC: 2893405. DOI: 10.4049/jimmunol.0900592. View