Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I–binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae. Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2Kb–restricted CD8+ T lymphocyte response upon immunotherapy with cyclophosphamide or anti–PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP–cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.

Follicular regulatory T (T) cells from lymph node germinal centers control follicular helper T (T) cell-dependent B cell activation. These scarce cells, often described and purified as CD25 cells, are thought to be derived from thymic regulatory T (T) cells. However, we observed that mouse T cells do not respond to interleukin-2 (IL-2), unlike T cells. Stringent immunophenotyping based on B cell lymphoma 6 (Bcl6), programmed cell death protein 1 (PD-1), and CXCR5 expression revealed that T cells are actually CD25, in mice and humans. Moreover, T cell characterization based only on CXCR5 and PD-1 high expression without excluding CD25 cells resulted in contamination with T cells. Transcriptome studies of CD4CXCR5PD-1Bcl6Foxp3CD25 T cells revealed that they express the IL-1 decoy receptor IL-1R2 and the IL-1 receptor antagonist IL-1Ra, whereas T cells express the IL-1R1 agonist receptor. IL-1 treatment expanded T cells in vivo and activated their production of IL-4 and IL-21 in vitro. T cells suppressed the IL-1-induced activation of T cells as efficiently as the IL-1 receptor antagonist Anakinra. Altogether, these results reveal an IL-1 axis in the T cell control of B cell responses and an IL-2/IL-1 dichotomy for T cell control of effector T cells versus T cell control of T cells.