Clonal expansion of vaccine-elicited T cells is independent of aerobic glycolysis

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Science Immunology  07 Sep 2018:
Vol. 3, Issue 27, eaas9822
DOI: 10.1126/sciimmunol.aas9822

Mitochondria fuel vaccine-induced T cells

Effective T cell responses to subunit vaccines administered with an adjuvant depend on a different set of signals than natural T cell responses to infectious microbes. Klarquist et al. compared the cytokine and metabolic requirements for clonal expansion of mouse CD8+ T cells responding to adjuvanted subunit vaccination or infection. In contrast to T cells responding to infection, T cells responding to vaccination were compromised in the absence of either IL-27 or IL-15 signaling and used mitochondrial function rather than aerobic glycolysis to support proliferation. These results demonstrate the existence of fundamental metabolic differences in CD8+ T cell responses to vaccines versus infection that need to be considered as part of the process of designing new vaccines.


In contrast to responses against infectious challenge, T cell responses induced via adjuvanted subunit vaccination are dependent on interleukin-27 (IL-27). We show that subunit vaccine–elicited cellular responses are also dependent on IL-15, again in contrast to the infectious response. Early expression of interferon regulatory factor 4 (IRF4) was compromised in either IL-27– or IL-15–deficient environments after vaccination but not infection. Because IRF4 facilitates metabolic support of proliferating cells via aerobic glycolysis, we expected this form of metabolic activity to be reduced in the absence of IL-27 or IL-15 signaling after vaccination. Instead, metabolic flux analysis indicated that vaccine-elicited T cells used only mitochondrial function to support their clonal expansion. Loss of IL-27 or IL-15 signaling during vaccination resulted in a reduction in mitochondrial function, with no corresponding increase in aerobic glycolysis. Consistent with these observations, the T cell response to vaccination was unaffected by in vivo treatment with the glycolytic inhibitor 2-deoxyglucose, whereas the response to viral challenge was markedly lowered. Collectively, our data identify IL-27 and IL-15 as critical to vaccine-elicited T cell responses because of their capacity to fuel clonal expansion through a mitochondrial metabolic program previously thought only capable of supporting quiescent naïve and memory T cells.

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