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CD4⁺ T cells classically recognize antigens that are endocytosed and processed in lysosomes for presentation on major histocompatibility complex (MHC) class II molecules. Here, endogenous Epstein-Barr virus nuclear antigen 1 (EBNA1) was found to gain access to this pathway by autophagy. On inhibition of lysosomal acidification, EBNA1, the dominant CD4⁺ T cell antigen of latent Epstein-Barr virus infection, slowly accumulated in cytosolic autophagosomes. In addition, inhibition of autophagy decreased recognition by EBNA1-specific CD4⁺ T cell clones. Thus, lysosomal processing after autophagy may contribute to MHC class II–restricted surveillance of long-lived endogenous antigens including nuclear proteins relevant to disease.