By integrating data on the immune profiles of healthy monozygotic and dizygotic twin pairs we estimated the variance in CD25 expression by naïve Th cells to be largely driven by genetic and shared early environmental influences. Nonetheless, the Th cell subset expanded in MS twins, which was also elevated in non-twin MS patients , emerged independent of the individual genetic makeup. These cells expressed CNS-homing receptors, exhibited a dysregulated CD25-IL-2 axis, and their proliferative capacity positively correlated with MS severity . Together, the pair-matched analysis of the extended twin approach allowed us to discern genetically- and environmentally- determined features of an MS-associated immune signature. Overall design: Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) of CD4+ T and myeloid cells in monozygotic twin pairs discordant for MS to obtain a comprehensive overview of epitopes, transcriptome and T cell receptor (TCR) clonotypes.