ABSTRACT: BACKGROUND: Using a combined in silico approach, we investigated the glycosylation of T cell epitopes and autoantigens. The present systems biology analysis was made possible by currently available databases (representing full proteomes, known human T cell epitopes and autoantigens) as well as glycosylation prediction tools. RESULTS: We analyzed the probable glycosylation of human T cell epitope sequences extracted from the ImmuneEpitope Database. Our analysis suggests that in contrast to full length SwissProt entries, only a minimal portion of experimentally verified T cell epitopes is potentially N- or O-glycosylated (2.26% and 1.22%, respectively). Bayesian analysis of entries extracted from the Autoantigen Database suggests a correlation between N-glycosylation and autoantigenicity. The analysis of random generated sequences shows that glycosylation probability is also affected by peptide length. Our data suggest that the lack of peptide glycosylation, a feature that probably favors effective recognition by T cells, might have resulted in a selective advantage for short peptides to become T cell epitopes. The length of T cell epitopes is at the intersection of curves determining specificity and glycosylation probability. Thus, the range of length of naturally occurring T cell epitopes may ensure the maximum specificity with the minimal glycosylation probability. CONCLUSION: The findings of this bioinformatical approach shed light on fundamental factors that might have shaped adaptive immunity during evolution. Our data suggest that amino acid sequence-based hypo/non-glycosylation of certain segments of proteins might be substantial for determining T cell immunity/autoimmunity.