Type I interferons (IFN) are pleiotropic cytokines that modulate both innate and adaptive immune responses. They have been used to treat autoimmune disorders, cancers, and viral infection and have been demonstrated to elicit differential responses within cells, despite sharing a single receptor. The molecular basis for such differential response has remained elusive. To identify mechanisms underlying differential type I interferon signaling, we used whole genome microarrays to measure longitudinal transcriptional events within human CD4+ T cells, treated IFN-2b or IFN-1a. We identified differentially regulated genes, analyzed them for the enrichment of known promoter elements and pathways, and constructed a network modules based on the weighted gene co-expression network analysis (WGCNA). WGCNA employs advanced statistical measures to find interconnected modules of correlated genes. Overall, differential responses to IFN in CD4+ T cells related to three dominant themes: migration, antigen presentation, and cytotoxic response. For migration, WGCNA identified subtype specific regulation of PRPF4B and EIF4A2, which work at various levels within the cell to affect the expression of the chemokine CCL5. WGCNA also identified SAMD9L as critical in subtype independent effects of IFN treatment. RNA interference of SAMD9L expression enhanced the migratory phenotype of activated T cells treated with IFN-, as compared to controls. Through the analysis the dynamic transcriptional events following differential IFN treatment, we were able to identify specific signatures and to uncover novel genes that may underpin the type I interferon response.