Analyzing the human T cell repertoire is possible thanks to sensitive techniques for its detection and characterization. Using such approaches, Mark Davis and his colleagues now find that CD4+ T cells in humans can recognize pathogens without prior exposure, owing to antigen cross-reactivity (Immunity 38, 373–383).

The researchers made peptide-MHC tetramer complexes incorporating peptides from self proteins, from various viruses or from tetanus toxin to determine the frequency of antigen-specific T cells in humans. They found CD4+ T cells capable of recognizing antigens that they had never previously encountered, and prior exposure to an antigen did not increase the frequency of T cells recognizing that antigen. Moreover, many of these pathogen-specific CD4+ T cells from unexposed individuals were phenotypically and functionally memory cells. Although the authors found similar frequencies of self peptide– or pathogen-specific CD4+ T cells in cord blood from unexposed infants compared with adults, the antigen-specific T cells in cord blood were naive, and not memory cells, which might contribute to the lesser ability of newborns to respond to infections.

The researchers next looked at influenza-specific T cells from two individuals who received the seasonal influenza vaccine and showed that T cells specific for an epitope in the viral hemagglutinin also recognized peptides from other microbes, and that the vaccine expanded cross-reactive memory T cells. These findings suggest that infection or immunization with a particular microbe can elicit cross-reactive CD4+ T cells that may help protect against pathogens to which an individual has had no prior exposure, and support the idea that environmental exposure to infectious agents can boost immune responses.