Antiviral memory phenotype T cells in unexposed adults

αβ T cells are an integral part of protective immunity against pathogens. After precursor cells arise in the adult bone marrow or fetal liver, they migrate to the thymus where they rearrange their T-cell receptor genes (TCR) and undergo selection on the basis of their interactions with ligands expressed by thymic stroma and other cells. Those that survive then exit the thymus to populate the peripheral immune compartment, where they patrol the blood and lymphoid systems. The composition of this pre-immune peripheral repertoire is critically important in determining the robustness of an immune response. In both mice and humans, the magnitude and diversity of a response are directly correlated with the frequency of precursor T cells. Equally relevant are the functional characteristics of these lymphocytes. Engagement of a specific antigen to the TCR activates signaling pathways in the naive T cell that result in cellular proliferation and the acquisition of particular effector functions. A portion of these persist following the resolution of infection and become memory cells. These memory cells can mount a faster and stronger response when they encounter the same antigen at a later time. As the molecular basis for TCR ligand interaction has become better defined, it is clear that some T cells can recognize multiple distinct ligands and therefore T-cell memory developed by exposure to one ligand may play a significant role in the response to a different antigen. Thus, there is an increasing focus on understanding how exposure to related or unrelated antigens influences the T-cell repertoire and impacts subsequent immunity. In this review, we discuss the issue of TCR cross-reactivity in the development of memory phenotype CD4(+) T cells and the implications for pathogen-specific responses. We review both the human and mouse data and discuss the therapeutic implications of these findings in the contexts of infection and vaccination.