Interpretation |Sun Yat-sen University: Pik3ip1, a novel immunonegative regulatory molecule, regulates the progression of autoimmune diseases by metabolic reprogramming to maintain the resting state of T cells

Autoimmune diseases are diseases in which the immune system attacks the body itself, causing local or systemic inflammation or tissue destruction
.
Due to the high prevalence and disability rates, autoimmune diseases have been considered the third most threatening disease to human health after cardiovascular diseases and tumors
.
However, the pathogenesis of autoimmune diseases is complex and has not been fully elucidated
.

Loss of immune tolerance of T cells is thought to be an important factor
in the development of autoimmune diseases.
Deletion of immune negative regulatory molecules such as CTLA-4 and PD-1 causes autoimmune diseases
.
However, compared with the research of such molecules in tumors, their research in autoimmune diseases is still in its infancy
.
At present, the approved drugs targeting negative immune regulatory molecules for the treatment of autoimmune diseases are very limited, and there is a risk of infection and tumor during use, so it is urgent to obtain new molecules of immune negative regulation that can effectively regulate autoimmune diseases and develop targeted therapeutic drugs
.

In a new study, the team of Professor Wang Zhi of the Affiliated Hospital of Stomatology of Sun Yat-sen University confirmed that the novel immune negative regulatory molecule Pik3ip1 helps maintain T cell metabolic homeostasis, and the loss of Pik3ip1 promotes the progression of
autoimmune diseases.
This study reveals the protective role of Pik3ip1 in the progression of autoimmune diseases and provides a basis for
targeting Pik3ip1 in the treatment of autoimmune diseases.

Previous studies by the authors have found that the negative immunoregulatory molecule Pik3ip1 in the tumor microenvironment can play a role
in promoting tumor growth by inhibiting T cell function.
However, the role and mechanism of Pik3ip1 in autoimmune diseases are currently unknown
.
The authors first found through clinical sample detection that the expression of Pik3ip1 in T cells of patients with a variety of autoimmune diseases was significantly lower than that in healthy people, and the expression of Pik3ip1 in T cells was closely related
to disease progression and treatment responsiveness.
Further exploring the phenotype of T cells in patients with autoimmune diseases, it was found that the downregulation of T cell Pik3ip1 expression was accompanied by increased T cell activation, effector secretion and inflammatory factors such as IL-17
.
In order to explore the reasons for the downregulation of T cell Pik3ip1 expression in patients with autoimmune diseases, the authors found that IL-21 can downregulate T cell Pik3ip1 expression
through the p38MAPK/ADAM17 axis through screening and in vitro experiments.

The authors further constructed an experimental autoimmune encephalomyelitis model (EAE) using cKO mice and control mice with T cell-specific knockout of Pik3ip1 to explore the role
of T cells Pik3ip1 in the progression of autoimmune diseases in vivo.
The results showed that cKO mice had a more severe disease phenotype
than control mice.
The number and proportion of inflammatory T cells in the spleen and central nervous system of cKO mice increased
.
Through further exploration, the authors found that abnormal activation of T cells due to deletion of T cells Pik3ip1 is achieved by hypoxia-inducible factor (Hif1α)-mediated metabolic reprogramming
.
In short, the deletion of Pik3ip1 in T cells causes the expression of Hif1α to be upregulated, resulting in a decrease in the level of cellular oxidative phosphorylation, an increase in the level of glycolysis, and excessive activation
of T cells.
This metabolic reprogramming and abnormal activation
caused by Pik3ip1 deletion of T cells can be effectively reversed by the use of Hif1α inhibitors.
The use of Hif1α inhibitors in mice can also effectively reverse the exacerbation of EAE disease caused by the deletion of T cells Pik3ip1 and the abnormal activation
of T cells.

In general, the pathogenic factor IL-21, which is abundant in patients with autoimmune diseases, can downregulate the expression of Pik3ip1 in T cells, and this study proposes and confirms that the new negative regulatory molecule Pik3ip1 acts on inflammatory circuits through metabolic reprogramming, and the Pik3ip1/Hif1α/glycolytic axis is a potential therapeutic target for autoimmune diseases
.