A high fat diet (HFD) has long been linked to immune dysfunction, including diminished numbers or reactivity of lymphocytes, increased susceptibility to infection, inhibited lymphocytes function during antigen-specific responses and developed oxidative stress. Whereas the molecular mechanistic events associated with immune deficiency remain to be fully determined. Using the DNA microarray system, we analyzed the gene expression patterns of lymphocyte related signal transduction proteins in jejunum of C57BL/6 mice in order to gain insight on the possible molecular mechanism by which HFD induced oxidative stress effects on signal transduction of lymphocytes. Results of present study showed that HFD induced oxidative stress and immunosuppression in jejunum. Antioxidant lipoic acid (LA) supplement ameliorated that HFD induced oxidative stress and immunosuppression by recovering transcriptional levels of the gene involved in B cell receptor, T cell differentiation signaling pathway, and free radical scavengers. The present study indicates that a HFD can induce chronic oxidative stress, suppress signal transduction of gut-associated lymphocytes, and lead to an inhibition of mucosal immunity.