bims-imseme 2022-06-05 papers

Issue of 2022‒06‒05
five papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

Immunometabolism. 2022 ;pii: e220013. [Epub ahead of print]4(2):

Mitochondrial Exhaustion of Memory CD4 T-Cells in Treated HIV-1 Infection.

People living with HIV (PLWH) who are immune non-responders (INR) to therapy are unable to restore their CD4 T-cell count and remain at great risk of morbidity and mortality. Here the mitochondrial defects that characterize memory CD4 T-cells in INR and causes of this mitochondrial exhaustion are reviewed. This review also describes the various reagents used to induce the expression of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), the master regulator of mitochondrial biogenesis, which can restore mitochondria fitness and CD4 T-cell proliferation in INR. Due to sustained heightened inflammation in INR, the mitochondrial network is unable to be rejuvenated and requires attenuation of mediators of inflammation to rescue mitochondria and CD4 T-cell counts in INR.

Keywords: CD4 T-cells; exhaustion; mitochondria; pgc1α

DOI: https://doi.org/10.20900/immunometab20220013

Front Immunol. 2022 ;13 839390

Alcohol Impairs Immunometabolism and Promotes Naïve T Cell Differentiation to Pro-Inflammatory Th1 CD4+ T Cells.

Patrick M McTernan, Danielle E Levitt, David A Welsh, Liz Simon, Robert W Siggins, Patricia E Molina.

CD4+ T cell differentiation to pro-inflammatory and immunosuppressive subsets depends on immunometabolism. Pro-inflammatory CD4+ subsets rely on glycolysis, while immunosuppressive Treg cells require functional mitochondria for their differentiation and function. Previous pre-clinical studies have shown that ethanol (EtOH) administration increases pro-inflammatory CD4+ T cell subsets; whether this shift in immunophenotype is linked to alterations in CD4+ T cell metabolism had not been previously examined. The objective of this study was to determine whether ethanol alters CD4+ immunometabolism, and whether this affects CD4+ T cell differentiation. Naïve human CD4+ T cells were plated on anti-CD3 coated plates with soluble anti-CD28, and differentiated with IL-12 in the presence of ethanol (0 and 50 mM) for 3 days. Both Tbet-expressing (Th1) and FOXP3-expressing (Treg) CD4+ T cells increased after differentiation. Ethanol dysregulated CD4+ T cell differentiation by increasing Th1 and decreasing Treg CD4+ T cell subsets. Ethanol increased glycolysis and impaired oxidative phosphorylation in differentiated CD4+ T cells. Moreover, the glycolytic inhibitor 2-deoxyglucose (2-DG) prevented the ethanol-mediated increase in Tbet-expressing CD4+ T cells but did not attenuate the decrease in FOXP3 expression in differentiated CD4+ T cells. Ethanol increased Treg mitochondrial volume and altered expression of genes implicated in mitophagy and autophagosome formation (PINK1 and ATG7). These results suggest that ethanol impairs CD4+ T cell immunometabolism and disrupts mitochondrial repair processes as it promotes CD4+ T cell differentiation to a pro-inflammatory phenotype.

Keywords: CD4+ T cell; alcohol; differentiation; glycolysis; immunometabolism; mitochondria

DOI: https://doi.org/10.3389/fimmu.2022.839390

Cancer Res. 2022 May 31. pii: canres.4052.2021. [Epub ahead of print]

Intracellular acetyl CoA potentiates the therapeutic efficacy of anti-tumor CD8+ T cells.

Snehanshu Chowdhury, Anwesha Kar, Debaleena Bhowmik, Anupam Gautam, Debashree Basak, Ishita Sarkar, Puspendu Ghosh, Deborpita Sarkar, Alvina Deka, Paramita Chakraborty, Asima Mukhopadhyay, Shikhar Mehrotra, Soumen Basak, Sandip Paul, Shilpak Chatterjee.

Effector CD8+ T cells rely primarily on glucose metabolism to meet their biosynthetic and functional needs. However, nutritional limitations in the tumor microenvironment can cause T cell hyporesponsiveness. Therefore, T cells must acquire metabolic traits enabling sustained effector function at the tumor site to elicit a robust anti-tumor immune response. Here, we report that IL-12-stimulated CD8+ T cells have elevated intracellular acetyl CoA levels and can maintain IFNγ levels in nutrient-deprived, tumour-conditioned media (TCM). Pharmacological and metabolic analyses demonstrated an active glucose-citrate-acetyl CoA circuit in IL-12-stimulated CD8+ T cells supporting an intracellular pool of acetyl CoA in an ATP-citrate lyase (ACLY)-dependent manner. Intracellular acetyl CoA levels enhanced histone acetylation, lipid synthesis, and IFNγ production, improving the metabolic and functional fitness of CD8+ T cells in tumors. Pharmacological inhibition or genetic knockdown of ACLY severely impaired IFNγ production and viability of CD8+ T cells in nutrient-restricted conditions. Furthermore, CD8+ T cells cultured in high pyruvate-containing media in vitro acquired critical metabolic features of IL-12-stimulated CD8+ T cells and displayed improved anti-tumor potential upon adoptive transfer in murine lymphoma and melanoma models. Overall, this study delineates the metabolic configuration of CD8+ T cells required for stable effector function in tumors and presents an affordable approach to promote the efficacy of CD8+ T cells for adoptive T cell therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-4052

J Clin Invest. 2022 Jun 01. pii: e160474. [Epub ahead of print]132(11):

Transforming dysfunctional CD8+ T cells into natural controller-like CD8+ T cells: can TCF-1 be the magic wand?

Hiroshi Takata, Lydie Trautmann.

HIV infection results in defective CD8+ T cell functions that are incompletely resolved by antiretroviral therapy (ART) except in natural controllers, who have functional CD8+ T cells associated with viral control. In this issue of the JCI, Perdomo-Celis et al. demonstrated that targeting the Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) pathway in dysfunctional CD8+ T cells led to gains in stemness phenotype, metabolic quiescence, survival potential, response to homeostatic γ-chain cytokines, and antiviral capacities, similar to profiles of functional CD8+ T cells in natural controllers. Although reprogramming might not sufficiently reverse the imprinted dysfunction of CD8+ T cells in HIV infection, these findings outline the Wnt/TCF-1 pathway as a potential target to reprogram dysfunctional CD8+ T cells in efforts to achieve HIV remission.

DOI: https://doi.org/10.1172/JCI160474

Cancer Discov. 2022 Jun 02. 12(6): 1405

PRODH2-Mediated Proline Metabolism Boosts CAR T-cell Effector Function.

Overexpression of PRODH2 augments CAR T-cell proliferation, effector function, and memory phenotype.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-054