The pathophysiology underlying the autoimmune disease type 1 diabetes (T1D) is poorly understood. Obtaining an accurate proteomic profile of the T helper cell population is essential for understanding the pathogenesis of T1D. Here, we performed in-depth proteomic profiling of peripheral CD4+ T cells in a pediatric cohort to identify cellular signatures associated with the onset of T1D. Using only 250 000 CD4+ T cells per patient, isolated from biobanked PBMC samples, we identified nearly 6000 proteins using deep-proteome profiling with LC-MS/MS data independent acquisition. Our analysis revealed an inflammatory signature in patients with T1D; this signature is characterized by circulating mediators of neutrophils, platelets, and the complement system. This signature likely reflects the inflammatory extracellular milieu, which suggests that activation of the innate immune system plays an important role in disease onset. Our results emphasize the potential value of using high-resolution LC-MS/MS to investigate limited quantities of biobanked samples to identify disease-relevant proteomic patterns. Proteomic profiles of 114 individuals have been deposited in a comprehensive portable repository serving as a unique resource for CD4+ T cell expression in the context of both health and T1D disease.