Science Advances Sun Yat-sen University's Wang Zhi team found that T cell metabolic reprogramming regulates the progression of autoimmune diseases and their therapeutic significance

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Metabolic changes can profoundly affect immune function and affect the progression and outcomes
of autoimmune diseases.
However, specific mechanisms and their therapeutic potential remain to be determined
.

On September 30, 2022, Sun Yat-sen University's Wang Zhi team published a research paper entitled "Regulation of autoimmune disease progression by Pik3ip1 through metabolic reprogramming in T cells and therapeutic implications" online at Science Advances.
The study found that phosphatidylinositol 3-kinase (PI3K) interacting protein 1 (Pik3ip1) is a newly discovered negative immunomodulator that is significantly downregulated in several major autoimmune diseases through a previously unidentified mechanism mediated
by the interleukin-21/p38 mitogen-activated protein kinase/a lysin and metalloproteinase-17 (ADAM17) pathways.

In experimental autoimmune encephalomyelitis (EAE) mouse models, the downregulation of Pik3ip1 in T cells led to a major metabolic shift from oxidative phosphorylation to aerobic glycolysis, leading to its overactivation and invasion disease progression
.
Inhibition of hypoxia-inducing factor 1α (Hif1α) or drug inhibition of glycolysis can reverse these phenotypes and greatly reduce the severity
of EAE.
Together, the study revealed the unrecognized role of Pik3ip1 in metabolic regulation, which significantly affects the inflammatory ring in the autoimmune environment, and identified Pik3ip1/Hif1α/glycolysis axis as a potential therapeutic target for autoimmune disease therapy
.

Autoimmune diseases include a group of diseases characterized by an adaptive immune system that responds to autoantigens, leading to local or systemic inflammation and tissue destruction
.
The underlying mechanisms of autoimmunity are still not fully elucidated, but it appears that the occurrence or worsening of autoimmune diseases is due to a loss
of immune tolerance.
T lymphocytes are the central role
in regulating the adaptive immune response.
Damage to T cell tolerance, which polarizes T cells to a highly active and pathogenic inflammatory phenotype, will lead to T cell/autoantibody-mediated autoimmune diseases
.
Therefore, in preclinical and clinical trials, there is an urgent need to develop therapies
aimed at enhancing T cell tolerance and inhibiting pathogenic inflammatory T cells against various T cell-mediated autoimmune diseases.
The mechanism by which T cells transform into inflammatory phenotypes is unclear
.
A deeper understanding of the external or intrinsic factors driving T cell polarization will help find new targets
in the treatment of autoimmune diseases.
Changes in the metabolic program of T cells are intricately linked
to their activation and inflammatory status.
Although there is growing evidence that aerobic glycolysis gives T cells a strong pro-inflammatory phenotype both transcriptionally and epigenetically, the molecular pathway of converting oxidative quiescent T cells into glycolytic pro-inflammatory T cells remains unclear
.
Negative immunomodulators, such as cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and lymphocyte activation gene-3 (LAG-3), are proteins that mediate negative signals of immune activation and block inappropriate immune responses
。 Pik3ip1 in a variety of autoimmune diseases is associated with more severe clinical diseases, poor treatment response, and T cell alteration of homeostasis (Figure from Science Advances) has been shown that during infection and tumors, negative immunomodulators are needed to inhibit glycolysis and drive oxidative metabolism
of T cells.
However, under autoimmune conditions, whether they are involved in T cell metabolic reprogramming has not been thoroughly studied
.
So far, only one drug targeting a negative immunomodulator (abatacept, a CTLA-4-Fc fusion protein) has been fully approved by the U.
S.
Food and Drug Administration for the treatment of several autoimmune diseases, but the response rate has not been satisfactory
.
Therefore, it is necessary
to deeply understand the basic mechanism of negative immunomodulators on the metabolism regulation of autoimmune diseases and find more effective alternative methods.
Phosphatidylinosine 3-kinase interacting protein 1 (Pik3ip1) is an upstream inhibitor of the phosphatidylinositol 3-kinase (PI3K) signaling pathway with a kringle domain on the cell surface, which contains a motif
homologous to the PI3K regulatory subunit p85.
Previous studies have reported that Pik3ip1 is highly expressed on naïve T cells (Tn) and rapidly decreases its expression after T cell activation, playing an important role
in modulating T cell-mediated responses.
Pik3ip1 was previously defined as a new tumor-negative immunomodulator that inhibits T cell-mediated anti-tumor responses
.
However, whether Pik3ip1 is involved in T cell metabolism regulation and its role in pro-inflammatory T cell polarization in autoimmune processes has rarely been studied
.
In this study, it was confirmed that downregulation of Pik3ip1 in T cells is prevalent in patients with autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS), and that the expression level of Pik3ip1 is highly correlated
with the severity of the disease and the efficacy of treatment 。 Mechanically, loss of Pik3ip1 expression leads to decreased oxidative phosphorylation (OXPHOS) and increased glycolysis of T cells, thereby promoting an inflammatory response and further exacerbating the initial onset of autoimmune diseases
in a hypoxia-inducing factor 1α (Hif1α) dependence.
In addition, the study found that overproduction of interleukin-21 (IL-21) in the autoimmune environment is upregulated by p38 mitogen-activated protein kinase (MAPK)-mediated depolymerin and metalloproteinase-17 (ADAM17), resulting in a break
in the functional domain of Pik3ip1.
These findings confirm that Pik3ip1 is a key regulator of metabolic homeostasis in T cells and highlight the importance of
the Pik3ip1/Hif1α/glycolysis axis in autoimmune diseases.

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