Enhanced signaling through the IL-2 receptor in CD8<sup>+</sup>T cells regulated by antigen recognition results in preferential proliferation and expansion of responding CD8<sup>+</sup>T cells rather than promotion of cell death

Adequate responsiveness of CD8+ T cell populations is of utmost importance for the efficacy of many vaccines and immunotherapeutic strategies against intracellular pathogens and cancer. In this study, we show in mouse models that the relative number of IL-2–producing cells within Ag-specific CD8+ T cell populations predicts the population expansion capacity upon challenge. We further demonstrate that IL-2 producers constitute the best responding subset. Notably, we show that elevated production of IL-2 by CD8+ T cells results in concomitant improved population expansion capacity and immunity. The amount of IL-2 produced on a per-cell basis essentially connects directly to the superior CD8+ T cell population expansion. Together, our findings identified that autocrine IL-2 production operates in a dose-dependent fashion to facilitate the expansion potential of Ag-specific CD8+ T cell populations, which may instigate ways to augment therapies depending on fit CD8+ T cells.

Section: Discussionsupporting

confidence: 93%

The Quantity of Autocrine IL-2 Governs the Expansion Potential of CD8+ T Cells

Redeker

Welten

Baert

et al. 2015

“…These results may indicate that memory CD8 ϩ T cells are in a partly anergic state in the absence of CD28 costimulation, which can be restored by IL-2. It has been reported previously that the majority of responding CD8 ϩ T cells during a recall response express IL-2 (64) and that IL-2 signals can significantly enhance recall responses (65,66). We hypothesize that the inability of the memory cells to produce IL-2 (Fig.…”

Section: Discussionmentioning

confidence: 86%

Control of Memory CD8+ T Cell Differentiation by CD80/CD86-CD28 Costimulation and Restoration by IL-2 during the Recall Response

Fuse

Zhang

Usherwood

2008

115

Memory CD8+ T cell responses have been considered to be independent of CD80/CD86-CD28 costimulation. However, recall responses are often severely blunted in CD28−/− mice. Whether this impairment represents a requirement for CD28 costimulation for proper memory CD8+ T cell development or a requirement during the recall response is unknown. Furthermore, how CD28 costimulation affects the phenotype and function of memory CD8+ T cells has not been characterized in detail. In this study, we investigate these questions by studying the role of the CD28 costimulatory pathway in memory CD8+ T cell responses to acute and persistent DNA virus infections. Memory CD8+ T cells against vaccinia virus (VV) infection which develop without CD28 costimulation exhibit lower expression of differentiation markers CD27 and CD122 (IL-15Rβ). These memory CD8+ T cells also fail to produce IL-2. Our data indicate that for an optimal recall response, CD28 costimulation is required both for T cell priming and also during the recall response. Similar requirements were observed for memory CD8+ T cell responses during persistent infection with murine gammaherpesvirus 68 (MHV-68) infection, indicating CD28 may play the same role in both acute and persistent infections. Finally, we show deficits in the recall response are restored by IL-2 signaling during recall, but not during priming. The data presented show that CD28 costimulation not only controls the magnitude of the primary response but also affects development of memory CD8+ T cells and is required during the recall response in addition to initial T cell priming.

“…Finally, in vivo tracking of IL-2-and IL-2R␣-deficient T cells has shown reduced T cell expansion relative to wild-type T cells without a major effect on T cell apoptosis or contraction (28,48). Conversely, T cells engineered to have enhanced IL-2R signaling show increased expansion in vivo with no evidence of increased apoptosis (8). Indeed, claims that IL-2 limits T cell expansion in vivo have generally been based on system-wide perturbations (33,49,50), which may produce unintended secondary effects.…”

Section: Il-2 and The Control Of Activation-induced Cell Death (Aicd)mentioning

confidence: 99%

IL-2, Regulatory T Cells, and Tolerance

Nelson

2004

Self Cite

515

378

IL-2 is a potent T cell growth factor that for many years was assumed to amplify lymphocyte responses in vivo. Accordingly, IL-2 has been used clinically to enhance T cell immunity in patients with AIDS or cancer, and blocking Abs to the IL-2R are used to inhibit T cell responses against transplanted tissues. It was later shown in mice that, unexpectedly, disruption of the IL-2 pathway results in lymphoid hyperplasia and autoimmunity rather than immune deficiency, indicating that the major physiological function of IL-2 is to limit rather than enhance T cell responses. This apparent paradox has recently been resolved with the discovery that IL-2 is critical for the development and peripheral expansion of CD4+CD25+ regulatory T cells, which promote self-tolerance by suppressing T cell responses in vivo. Our new understanding of IL-2 biology prompts a re-evaluation of how best to clinically manipulate this important immunoregulatory pathway.