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Mitochondrial Transplantation promotes protective effector and memory CD4⁺ T cell response during Mycobacterium tuberculosis infection and diminishes exhaustion and senescence in elderly CD4⁺ T cells.

ABSTRACT: Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (M.tb), remains a significant health concern worldwide, especially in populations with weakened or compromised immune systems, such as the elderly. Proper adaptive immune function, particularly a CD4⁺ T cell response, is central to host immunity against M.tb. Chronic infections, such as M.tb, as well as aging promote T cell exhaustion and senescence, which can impair immune control and promote progression to TB disease. Mitochondrial dysfunction contributes to T cell dysfunction, both in aging and chronic infections and diseases. Mitochondrial perturbations can disrupt cellular metabolism, enhance oxidative stress, and impair T-cell signaling and effector functions. This study examined the impact of mitochondrial transplantation (mito-transfer) on CD4⁺ T cell differentiation and function using aged mouse models and human CD4⁺ T cells from elderly individuals. Our study revealed that mito-transfer in naïve CD4⁺ T cells promoted the generation of protective effector and memory CD4⁺ T cells during M.tb infection in mice. Further, mito-transfer enhanced the function of elderly human T cells by increasing their mitochondrial mass and modulating cytokine production, which in turn reduced exhaustion and senescence cell markers. Our results suggest that mito-transfer could be a novel strategy to reestablish aged CD4⁺ T cell function, potentially improving immune responses in the elderly and chronic TB patients, with a broader implication for other diseases where mitochondrial dysfunction is linked to T cell exhaustion and senescence.

SUBMITTER: Headley CA

PROVIDER: S-EPMC10849707 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Mitochondrial Transplantation promotes protective effector and memory CD4+ T cell response during Mycobacterium tuberculosis infection and diminishes exhaustion and senescence in elderly CD4+ T cells.

Headley Colwyn A CA Gautam Shalini S Olmo-Fontanez Angelica A Garcia-Vilanova Andreu A Dwivedi Varun V Schami Alyssa A Weintraub Susan S Tsao Philip S PS Torrelles Jordi B JB Turner Joanne J

bioRxiv : the preprint server for biology 20240127

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (M.tb), remains a significant health concern worldwide, especially in populations with weakened or compromised immune systems, such as the elderly. Proper adaptive immune function, particularly a CD4+ T cell response, is central to host immunity against M.tb. Chronic infections, such as M.tb, as well as aging promote T cell exhaustion and senescence, which can impair immune control and pr ...[more]

PMID: 38328206

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Project description:In Type 1 Diabetes (T1D), CD4+ T cells initiate autoimmune attack of pancreatic islet β cells. Importantly, bioenergetic programs dictate T cell function, with specific pathways required for progression through the T cell lifecycle. During activation, CD4+ T cells undergo metabolic reprogramming to the less efficient aerobic glycolysis, similarly to highly proliferative cancer cells. In an effort to limit tumor growth in cancer, use of glycolytic inhibitors have been successfully employed in preclinical and clinical studies. This strategy has also been utilized to suppress T cell responses in autoimmune diseases like Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA). However, modulating T cell metabolism in the context of T1D has remained an understudied therapeutic opportunity. In this study, we utilized the small molecule PFK15, a competitive inhibitor of the rate limiting glycolysis enzyme 6-phosphofructo-2-kinase/fructose-2,6- biphosphatase 3 (PFKFB3). Our results confirmed PFK15 inhibited glycolysis utilization by diabetogenic CD4+ T cells and reduced T cell responses to β cell antigen in vitro. In an adoptive transfer model of T1D, PFK15 treatment delayed diabetes onset, with 57% of animals remaining euglycemic at the end of the study period. Protection was due to induction of a hyporesponsive T cell phenotype, characterized by increased and sustained expression of the checkpoint molecules PD-1 and LAG-3 and downstream functional and metabolic exhaustion. Glycolysis inhibition terminally exhausted diabetogenic CD4+ T cells, which was irreversible through restimulation or checkpoint blockade in vitro and in vivo. In sum, our results demonstrate a novel therapeutic strategy to control aberrant T cell responses by exploiting the metabolic reprogramming of these cells during T1D. Moreover, the data presented here highlight a key role for nutrient availability in fueling T cell function and has implications in our understanding of T cell biology in chronic infection, cancer, and autoimmunity.

Dataset Information

Mitochondrial Transplantation promotes protective effector and memory CD4⁺ T cell response during Mycobacterium tuberculosis infection and diminishes exhaustion and senescence in elderly CD4⁺ T cells.

Publications

Mitochondrial Transplantation promotes protective effector and memory CD4<sup>+</sup> T cell response during <i>Mycobacterium tuberculosis</i> infection and diminishes exhaustion and senescence in elderly CD4<sup>+</sup> T cells.

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