Thioredoxin (TRX) is a ubiquitous oxidoreductase with strong co‐cytokine, chemoattractant and anti‐apoptotic activities. TRX expression was found to be particularly elevated in the intestinal mucosa, where its physiologic function is entirely unknown. Here, we demonstrate a high level of TRX expression in lamina propria T cells (LP‐T) as opposed to autologous peripheral blood T lymphocytes (PB‐T). Addition of recombinant human TRX (rhTRX) to PB‐T enhances TRX gene expression. This autoregulation involves the calcineurin signaling pathway, as rhTRX antagonizes the cyclosporine A (CsA)‐ and tacrolimus‐mediated suppression of TRX gene expression. Similarly, rhTRX reverses the suppression of IL‐2 mRNA production by CsA and enhances cytokine production preferentially in prestimulated cells. The differential TRX expression in LP‐T versus PB‐T may thus contribute to the high‐level, CsA‐resistant IL‐2 production characteristic for CD2‐stimulated LP‐T. Inversely, inactivation of TRX in LP‐T through inhibition of TRX reductase abolishes cytokine gene expression. TRX may play a key role in the specialized intestinal microenvironment in amplifying immediate immune responses of LP‐T whenever appropriate costimulation of LP‐T is provided.