Activation of virtual memory CD8+ T cells specific for self antigens requires antigen presentation by CD11c+ cells

Abstract

Abstract Even in experimentally naïve mice, a significant fraction of CD8+ T cells express CD44, a marker associated with previous exposure to cognate antigen. Many of these cells express additional hallmarks of the memory phenotype, leading to questions about their specificity, development, and functional relevance. It has been suggested that lymphopenic conditions experienced by early T cells in prenatal/neonatal mice can give rise to these unexpected “virtual” memory T cells. However, their antigen specificity remains largely unknown. Here, we report several peptide sequences derived from self antigens, which are capable of eliciting robust interferon gamma (IFNγ) secretion in CD8+ T cells isolated from naïve mice. Only CD44+ (memory phenotype), and not CD44− (naïve phenotype) T cells show this unexpected self-reactivity, and the antigens are cross presented by professional antigen-presenting cells (pAPCs) but are not presented to T cells by non-pAPCs expressing these antigens. Interestingly, antigen donor cells pretreated with IFNγ also failed to stimulate these T cells. The implications of having such self-reactive memory-phenotype T cells in circulation remain unclear, although their role in autoimmunity and self-tolerance can be imagined. There is also the possibility that such responses are a manifestation of immunological nihilism.