The immune and nervous systems are two important regulatory systems to maintain the internal environment of the body. The nervous system controls the function of the immune system, and the immune system can regulate the nervous system through cytokines. Recent studies have shown that the immune inflammatory response of the brain plays a key role in the pathogenesis of several central nervous system diseases, including schizophrenia. Although the pathogenesis of schizophrenia is not well established, dopamine has been considered to be related to schizophrenia for a long time, with ample preclinical evidence supporting this hypothesis ^[1][2][3][28,29,30]. However, the mechanism of how dopamine causes schizophrenia remains unclear, and the therapeutic effect of antipsychotic and anti-dopamine drugs has not been satisfactory in clinical treatment. With the advance in research on schizophrenia, the theory of neuroinflammation has become increasingly recognized. The vulnerability-stress model, first proposed in the last century, emphasizes the role of stress in the onset of schizophrenia ^[4][31]. In addition, the vulnerability-stress-inflammation model proposed by Müller indicates that inflammation plays an important role in the pathogenesis of schizophrenia ^[5][8]. The mechanism of neuroinflammation involved in the pathophysiological process of schizophrenia is complex, and it mainly affects glutamate metabolism, inducing oxidative stress, neuronal apoptosis, and so onetc. Inflammation of the CNS is usually mediated by microglia, cytokines, astrocytes and immune cells (such as T cells). Microglia cells are the immune cell in the CNS, accounting for about 15% of the total CNS cells ^[6][32]. Microglia cells are sensors of cytokines, which play an important regulatory role in the CNS and are also the first line of defense against CNS infection ^[7][33]. At the end of the 20th century, Bayer et al. found that activated microglia in the frontal cortex and hippocampus increased significantly in 14 patients with schizophrenia when compared to 13 normal subjects ^[8][34]. Similar studies reported that microglia in dorsolateral prefrontal cortex, upper-temporal-lobe gray matter and anterior cingulate gyrus gray matter were significantly activated in patients with schizophrenia ^[9][35]. Uranova et al. observed the increase of activated microglia in the brain of patients with schizophrenia by electron microscope ^[10][36]. In addition to microglia, cytokines also have a great impact on schizophrenia. There have been many studies on the changes of cytokine levels in patients with schizophrenia. No marker for the diagnosis, treatment or disease progression has been established for schizophrenia so far. Cytokines are some of the key candidates in this research field, and Patel et al. have published a comprehensive review on this topic ^[11][37].

Infection and immunity have long been the focus of research on the etiology of schizophrenia. Intrauterine infection can increase the risk of mental illness and is often associated with early events in brain development ^[12][38]. A number of studies have found that there is an increased incidence of schizophrenia in people who were prenatally exposed to viral and bacterial infections and Toxoplasma gondii ^[13][14][15][39,40,41]. Most previous studies have been based on epidemiological surveys to find correlation between prenatal infection and neurodevelopmental outcomes in offspring ^[16][42]. However, with further research, the underlying mechanism of such correlation is becoming clearer. Exogenous infections can have direct and indirect effects on the fetal brain, resulting in varying degrees of neurological damage. The classic TORCH is an abbreviation for a type of infection that can cause severe brain malformation in fetuses and increase their risk of developing mental disorders ^[17][43]. In addition, maternal immune activation (MIA) may affect fetal brain development, thereby increasing their risk of developing schizophrenia. Studies suggest that maternal immunity will release inflammatory mediators after activation through maternal blood or amniotic fluid and affect fetal CNS development ^[18][44]. MIA can induce a variety of cytokine changes in the fetal brain, but the effect of these changes on the fetal brain is still poorly understood ^[19][20][45,46]. Interestingly, in animal studies, the offspring of mothers injected with IL-2 developed schizophrenia-like symptoms ^[21][47].

The Treg cell is the main cell type in maintaining immune homeostasis, including the innate and adaptive immune balance. The important role of IL-2 in the production of Treg cells has previously been described. In CNS, Tregs mainly regulate the neuroimmune interaction between astrocytes and microglia ^[22][48]. Impaired Treg cells induce astroglial overactivation and microglial pruning in schizophrenia ^[23][49]. Foxp3 is the main regulator of Treg cells and is very important for their development and inhibition ^[24][50]. Reduced CD4+/CD25+/Foxp3+-expressing Tregs with increased proinflammatory response in patients with schizophrenia were reported by Corsi-Zuelli last year ^[25][51].

Furthermore, Corsi-Zuelli et al. proposed the H-Treg hypothesis, which states that decreased Treg function could provide a missing link between low-level systemic inflammation and abnormal central glial regulation in psychosis ^[23][49]. The reason for supporting this hypothesis is that studies found that low-dose methotrexate improved the positive symptom scores in patients with schizophrenia when compared to a placebo group ^[26][52]; this result may be due to reset systemic regulatory T-cell control of immune signaling. These results suggest that restoring Tregs’ function might be a novel therapeutic target in schizophrenia.

3. Possible Effects of IL-2 in Schizophrenia

The effect of IL-2 has been widely studied in different aspects of schizophrenia. As early as the last century, studies had suggested a correlation between IL-2 and schizophrenia. IL-2 can affect many pathological processes which are related to the pathogenesis of schizophrenia, such as the Glu neurotransmitter system. Studies have shown that IL-2 can induce paroxysmal firing in the hippocampal structure of rats and affect the synthesis and release of Glu and GABA in hippocampal neurons. In addition, in vitro studies have shown that IL-2 can cause an increase in Glu immune response neurons and a decrease GABA in immune-response neurons ^[27][53]. IL-2 exerts its biological effect by binding the IL-2 receptor on the cell membrane. It acts not only in the immune response of the body, but also in some physiological or pathological processes of the CNS as a neural mediator ^[28][54]. Denicoff et al. performed systematic treatment of IL-2 activated killer cells in 44 patients with metastatic cancer ^[29][55]. The results showed that, among the 44 patients, 15 had serious behavioral changes, and half of the patients had serious cognitive changes. IL-2 had a dose–response relationship with neuro-behavioral changes. In an study, at a low dose, 4 of 19 patients showed schizophrenic symptoms, while at a high dose, 10 of 24 patients showed symptoms, and the symptoms of all patients disappeared after stopping treatment ^[30][56]. The mechanism for this effect has not been explored, but it might be due to IL-2-mediated cytotoxicity. Furthermore, Schwarz et al. analyzed the relationship between IL-2 and susceptibility genes for schizophrenia and found that there was a significant association between the IL-2–330TT genotype and schizophrenia in 230 patients with schizophrenia (χ² = 7.418, df = 2 and p = 0.024) ^[31][57]. According to previous in vitro studies, IL-2–330TT genotype polymorphism was shown to be related to IL-2 level ^[32][58]. Another study explored the relationship between IL-2RG gene and schizophrenia. Overall, mRNA expression was detected in the peripheral blood of 66 patients with schizophrenia and 99 healthy subjects. The results showed that, compared with the control group, the expression of IL-2RG mRNA in patients’ peripheral blood was upregulated (patients vs. controls, median [interquartile range]: 2.080 [3.428–1.046] vs. 0.324 [0.856–0.000], p < 0.0001), suggesting that the altered immune response in schizophrenia might be related to the overexpression of IL-2RG ^[33][59]. Taken together, these studies suggest a potential genetic link between IL-2 and schizophrenia.