Obesity can compromise immune response and immune surveillance. Recent studies have linked obesity with systemic T cell senescence and thymus involution. However, these studies failed to distinguish the influence of obesity from the influence of diet composition on premature T cell senescence. High-fat diet (HFD) can influence the immunity of gut-associated lymphoid tissue (GALT) preceding the onset of obesity. Despite GALT is sensitive to the changes in the dietary composition and metabolic status, it still remains elusive how HFD and obesity contribute to T cell senescence in the GALT. In this study, we illustrated the interplay of the HFD, obesity and intestinal immunity by comparing the immune features of diet-induced obese (DIO) to those of diet-resistant (DR) mice. As expected, DIO mice exhibited increased serum lipid levels and liver steatosis whereas dyslipidemia was absent in DR mice. DIO mice demonstrated a shift from naïve to effector-memory (EM) phenotype in the T cells derived from the spleens and PPs. Moreover, DIO mice showed up-regulation of PD1 and KLRG1 on the T cells. Similar but mild trends were observed in the naïve and EM T cells from DR mice. Furthermore, we proved that the senescent-like changes in splenic and PPs-derived T cells positively correlated with the serum lipid concentrations. Taken together, our results indicate that HFD components function synergistically with dyslipidemia to induce T cell senescence in the GALT. Copyright © 2021 Elsevier Inc. All rights reserved.