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Single-cell analysis by mass cytometry reveals metabolic states of early-activated CD8+ T cells during the primary immune response

Levine & Hiam-Galvez et al. Immunity. (2021)

Cells utilize distinct energy sources for particular functions, whether that’s long-term survival, rapid growth, or robust activation. Similar to how our bodies use sugar for a short-term energy boost and fat for long-term energy storage, it was believed that T cells did the same. Prior studies suggested that the activation of T cells required a shift in metabolic states from fatty acid oxidation to glycolysis, but this was not measured at the single-cell level.

To address this, Levine and Hiam-Galvez et al. used an 43-marker mass cytometry panel to characterize the metabolic profiles of CD8 T cells over 9 days in a mouse model of acute bacterial infection with Listeria monocytogenes. Infection clearance can give us clues as to what a successful immune response looks like. By understanding the metabolic profile of early-activated T cells in infection clearance, we can better identify early signals of effective T cell activation in other settings.

They found that early-activated T cells maximize expression of both glycolytic and oxidative metabolic proteins within the same cell, contrary to conclusions drawn from previous analyses using bulk T cells. They also identified cellular markers associated with the transition from naive to short-lived effector states, characterized by the transition from CD62L, CD127, and TCF1 expression towards KLRG1, CD44, and T-bet expression. Unsupervised analysis revealed a unique cluster of ICOS-expressing, highly proliferative cells at day 4 that comprised nearly 20% of the total CD8 T cell population by day 5 and almost completely disappeared by day 7, corresponding with the timing of infection clearance in this model.

Early-activated T cells maximize expression of both glycolytic and oxidative metabolic proteins within the same cell

The authors then applied this metabolic profiling to the analysis of CAR T cells in PBMC samples from two patients with advanced non-Hodgkin’s lymphoma treated with axi-cel (axicabtagene ciloleucel). Using a 36-marker panel, the researchers found that axi-cel CAR T cells express glycolytic and oxidative metabolic proteins as well as ICOS at the time of infusion. By day 7, the expression of most metabolic proteins was severely reduced within the CAR T cells.

This method for single-cell metabolic profiling provides a new approach for tracking of CAR T cell activation in patient blood and can provide data for personalizing re-dosing strategies. This methodology can also be applied to other cells of interest, such as CAR Tregs, and other blood cancers.

Reference Citation: Levine LS, Hiam-Galvez KJ, Marquez DM, Tenvooren I, Madden MZ, Contreras DC, Dahunsi DO, Irish JM, Oluwole OO, Rathmell JC, Spitzer MH. Single-cell analysis by mass cytometry reveals metabolic states of early-activated CD8+ T cells during the primary immune response. Immunity. 2021 Apr 13;54(4):829-844.e5. doi: 10.1016/j.immuni.2021.02.018.

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Illustration. In the center is a grey mass labeled "tumor" under a magnifying glass. Inside the tumor are three grey cells all with "zzz" above them. Outside the magnifying glass (and therefore outside the tumor) in the four corners are different depictions. Top left shows three red cells and is labeled "novel T cell clones". Top right shows a lymph node with red T cell zones and the words "LN trafficking required". Bottom right shows two red T cells in a blood vessel labeled "LAG-3 and CD8+" with the words "peripheral biomarkers". Bottom left shows a spleen with the same grey, sleeping T cells. There's a red lightning bolt and the words "impaired systemic immune response in cancer".

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