Virus-Specific CD4+ Memory-Phenotype T Cells Are Abundant in Unexposed Adults

Although T cell memory is generally thought to require direct antigen exposure, we found an abundance of memory-phenotype cells (20%–90%, averaging over 50%) of CD4+ T cells specific to viral antigens in adults who had never been infected. These cells express the appropriate memory markers and genes, rapidly produce cytokines, and have clonally expanded. In contrast, the same T cell receptor (TCR) specificities in newborns are almost entirely naïve, which might explain the vulnerability of young children to infections. One mechanism for this phenomenon is TCR cross-reactivity to environmental antigens, and in support of this, we found extensive cross-recognition by HIV-1 and influenza-reactive T lymphocytes to other microbial peptides and expansion of one of these after influenza vaccination. Thus, the presence of these memory-phenotype T cells has significant implications for immunity to novel pathogens, child and adult health, and the influence of pathogen-rich versus hygienic environments. ▸ Healthy adults have memory cells specific to unexposed foreign antigens ▸ Pre-existing memory-phenotype cells present in adults are absent in newborns ▸ HIV-1- and influenza-specific T cells cross-react with microbial peptides ▸ Influenza vaccination induces cross-reactive T cell expansion