Common gamma chain (γc) cytokines differentially potentiate TNFR family signaling in antigen-activated CD8+ T cells

Abstract

BackgroundSeveral members of the common gamma chain (gc) cytokine family are already approved (IL-2) or actively being developed as vaccine adjuvants and cancer immunotherapies. Studies have indicated that co-administration of gc cytokines may enhance the efficacy of immunotherapies that function via direct activation of co-stimulatory T cell receptors. To define the specific influence of gc cytokines on the co-stimulatory capacity of CD8+ T cells and identify combinations with synergistic potential, we investigated the direct impact of gc cytokines on the differentiation and transcriptional profile of recently antigen-primed CD8+ T cells.MethodsNaïve CD8+ T cells were activated with peptide-pulsed APCs. After 48 hours, CD8+ T cells were harvested and re-cultured in media supplemented with IL-2, IL-4, IL-7, IL-15 or IL-21. After 24 hours, cells were analyzed by cytokine bead array, flow cytometry, and mRNA micro-array. Gene networks responsible for specific CD8+ T cell functions were constructed through literature-meta review and publicly available annotation databases. Gene expression data from the experimental groups was imported into this network to visualize the impact of each gc cytokine on the functional polarization of recently-activated CD8+ T cells.ResultsAmong the gc cytokines, IL-2 induced the greatest increase in the expression of co-stimulatory receptors in recently-activated CD8+ T cells. IL-2 increased significantly expression of 4-1BB, GITR, ICOS and OX40, at both the transcriptional and protein level. IL-2 also drove the greatest increase in cellular proliferation and the most robust shift towards a pro-survival phenotype, compared with the other gc cytokines. Both IL-4 and IL-21 enhanced expression of cytotoxic effector proteins, but drove distinct phenotypic polarizations, Th2/Tc2 and NK-like, respectively.ConclusionsOverall, these observations suggest that among gc cytokines, IL-2 may be uniquely capable of synergizing with therapeutic strategies that combine immunization with agonists of co-stimulatory T cell receptors. Previous studies have shown that the timing of IL-2 treatment relative to immunization plays a key role in defining the CD8+ T cell response, and the findings from this study indicate that administration of exogenous IL-2 shortly after the initial antigen-priming event has concluded may augment the receptivity of these cells to subsequent TNFR co-stimulation.

Efficacy-enhanced and cytokine release syndrome-attenuated anti-CD7 universal chimeric antigen receptor-T cell therapy for relapsed/refractory CD7-positive hematological malignancies: A phase I clinical study

“…Additionally, in effector CD8 + T cells, IL-6 is a master regulator of IL-21. Quite different from the results of a previous nding that incorporating a truncated IL-2 receptor β chain to a CAR induced IL-21 signaling 37 , incorporating γc in our study reduced IL-21 level as well as its downstream targets, IL-18R1, IL18RBP, and IL18RAP. The response timing of activated CD8 + T cells to the γc cytokines is critical considering the study by Hinrichs and colleagues who showed that when exogenous IL-21 was added to the culture media during antigen priming, acquisition of effector functions and induction of granzyme B were inhibited, whereas exogenous IL-2 and IL-15 had an opposite effect.…”

Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4+ T Cells

“…An increase in STAT5 phosphorylation confirmed activation of the IL-2 pathway in CD4 + effector TILs in both untreated and αCTLA-4-treated tumors in comparison to CD4 + T cells in the LN ( Figure 4 D). Further analysis of T cell activation markers revealed increased expression of CD69, CD44, GITR (Glucocorticoid-Induced TNFR-Related Protein) and CD38 upon αCTLA-4 treatment, of which only GITR ( McNamara et al, 2014 ) was decreased by IL-2 deprivation relative to controls. PD-1 expression was consistently increased and the negative co-stimulatory molecule CD101 decreased ( Schey et al., 2016 ) in all αCTLA-4 treated groups regardless of IL-2 presence ( Figures 4 E and S4 D).…”

Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice

“…Treatment with an agonist aOX40 mAb directly stimulated CD4 and CD8 T cells and induced their expansion, differentiation, and up-regulation of prosurvival molecules (7)(8)(9)(10)(11)(12). Moreover, OX40 ligation promoted the generation of long-lived memory CD8 T cells and enhanced their function.…”