Meta-inflammation in type 2 diabetes mellitus: unveiling the role of aberrant CD4+ T cells and pro-inflammatory cytokine networks
Shubham K. Shaw, Soumya Sengupta, Rohila Jha, Chandrasekhar Pattanaik, Harapriya Behera, Prakash K. Barik, Dayanidhi Meher, Rajlaxmi Sarangi, Satish Devadas
Abstract
This study aimed to investigate the causal or casual relation between dysregulated glucose metabolism and meta-inflammation in type 2 diabetes mellitus (T2DM), and more importantly the mediators and cellular sources for this meta-inflammation. We examined whether T2DM meta-inflammation is driven by aberrant, inflamed T-helper cells and if there was a direct link to HbA1c levels. Flow cytometry data revealed TNF-α−secreting effector CD4 + T cells as key contributors to inflammation, while memory T cells secreting GM-CSF and IL-17 escalated and maintained meta-inflammation. Crucially, these cytokines were present even in the “resting CD4 + T cells,” reflecting an aberrant, low-grade, chronically activated, and inflamed immune system. Significantly, higher antibody isotype levels further substantiated these findings as proof of concept for sustained and inflamed APC-T cell-B cell nexus. while reduced IL-10 levels reflected a shift towards pro-inflammatory bias. Functional assays, phospho-protein expression, ex-vivo inhibitor studies, and confocal microscopy confirmed that basal meta-inflammation in T2DM is exclusively mediated by multiple T-helper cell phenotypes via the TNF-α/STAT-3-signaling axis. Plasma cytokine and antibody isotyping were profiled using multiplex immunoassays from undiluted plasma. Taken together, these findings suggest that unchecked cytokine secretion, inflamed T-helper subsets, unwarranted antibody isotypes, and so forth, may contribute to organ damage by further amplifying innate and adaptive immune responses. Monitoring inflammatory cytokines, antibody isotypes, and T-helper cell subsets could significantly mitigate organ damage in T2DM, offering a more comprehensive approach to disease management. Thus, this study highlights the importance of not only achieving metabolic control during T2DM treatment but also monitoring and regulating immune homeostasis.