Type 1 diabetes (T1D) is an autoimmune disease that prompted by autoreactive T cells, leading to the destruction of pancreatic β cells [1]. Individuals with T1D require a lifelong reliance on exogenous insulin, which places a significant strain on both patients and healthcare resources [2]. Over the past century, researchers have explored various therapies aiming to reverse the pathogenesis of T1D and reduce insulin dependency [3]. T1D involves a complex interplay of genetic and environmental factors [4], eventually resulting in the breakdown of immunological tolerance. As a result, immunomodulation-based treatments have emerged as promising strategies. However, the road to a T1D cure still demands extensive research to uncover the underlying immunopathological mechanisms [5,6]. Notably, in the initial year and early stages of T1D, the immune response experiences dynamic changes, particularly during the peri-remission phase [7], offering a unique opportunity to find potential therapeutic targets for reinstating the equilibrium among lymphocyte populations and serves as an optimal treatment window for immune therapies [[8], [9], [10]].

Signal transducer and activator of transcription 3 (STAT3) is one of the seven members of the STAT protein family, playing a crucial role in regulating T cells and STAT3 gain-of-function (GOF) syndrome is recently recognized as an autosomal dominant primary immune regulatory disorder [11]. Patients harboring germline STAT3 GOF variants can exhibit early-onset autoimmunity, lymphoproliferation, increased susceptibility to infections, and growth failure [[12], [13], [14]]. Over the past seven years, at least 191 patients with STAT3 Gain-of-Function (GOF) mutations have been documented [15] and recent evidence related the possible upregulation of CD57+ CD8+ T cells to this disease [16]. Interestingly, this particular population of CD8+ T cells has also been observed to increase in several autoimmune disorders, including rheumatoid arthritis (RA) [17], Graves’ disease [18] and systemic lupus erythematosus (SLE) [19], suggesting potential involvement in autoimmunity. Diggins et al. established a positive link between the presence of CD57-expressing exhausted-like CD8 T cells and the therapeutic response of alefacept treatment in T1D patients [20]. Similarly, Yeo et al. identified a positive correlation between the presence of β cell-specific effector memory CD8+ T cells expressing CD57 and changes in C-peptide levels among subjects under 12 years of age [21]. Yet, despite these insights, CD57+ CD8+ T cells retain their status as a highly diverse subset, with their precise role and regulation in T1D progression remain elusive.

The expansion of CD57+ CD8+ T cells is a multifactorial process, which may involve proinflammatory cytokines such as IL-15 that are elevated in chronic HIV infection [22]. In vitro studies have shown that IL-15 exposure specifically promotes the development of CD57+ CD8+ T cells [23]. The expanded CD8+ T cells are likely to be reactive to cytomegalovirus (CMV) [[24], [25], [26]] and express C-X3-C chemokine receptor 1 (CX3CR1) which identifies a population of long-lived effector memory cells with lytic granules and cytolytic capacity [23,[27], [28], [29]]. CXCL12, also known as stromal cell-derived factor-1 (SDF-1), along with its receptor CXCR4, plays a crucial role in regulating the immune response [30]. Several autoimmune conditions, including Sjögren's syndrome [31], psoriasis [32], multiple sclerosis [33], RA [34], SLE [35], and inflammatory bowel disease [35], exhibit heightened expression of CXCL12. Blocking the CXCL12-CXCR4 axis has shown promising results in delaying the onset or slowing the progression of inflammatory diseases [36,37]. However, whether CXCL12 drives the proliferation and function of peripheral CD57+ CD8+ T cells in patients with T1D, as well as its underlying mechanisms, are still unclear.

Here we found that the peripheral CD57+ CD8+ T cells increased in a T1D patient with STAT3 mutation and further characterized those cells in a cohort of T1D patients with different remission status, revealing that they were highly enriched in patients with new-onset T1D, while their levels decreased in patients during remission status. Our longitudinal cohort studies suggest that the presence of CD57+ CD8+ T cells may serve as a predictor for the deterioration of β-cell function in T1D patients. Phenotyping and functional assays demonstrated that CD57+ CD8+ T cells, exhibited a terminally differentiated phenotype with high expression of the cytolytic enzyme granzyme B (GZMB) and pro-inflammatory cytokines, were poised for effector function and had enhanced intracellular glucose uptake and decreased fatty acid uptake as metabolic reprogramming. In addition, in vitro studies showed that CXCL12 could induce the expansion of CD57+ CD8+ T cells, enhance their activity via Erk signaling pathway. And in vivo treatment with the CXCR4 antagonist-LY2510924 effectively reduced hyperglycemia and ameliorated T1D progression in the streptozotocin (STZ)-induced T1D mouse model. Notably, the changes of serum CXCL12 concentrations were also found in individuals during the peri-remission phase of T1D. Our findings provide a mechanistic link between the expansion, activation, and persistence of CD57+ CD8+ T cells in the context of T1D and this may offer promising avenues for exploring therapeutic targets to prevent autoimmunity in T1D immunotherapy.