Credit: NPG

It is generally believed that the development of pathogen-specific memory T cells requires previous exposure to the pathogen. However, a new study by Mark Davis and colleagues suggests that virus-specific memory-like CD4+ T cells can be abundant in humans who have never previously been infected with, or vaccinated against, the virus in question.

exposure to cross-reactive environmental antigens may drive the development of virus-specific memory T cells in uninfected individuals

The authors used tetramers specific for peptide epitopes presented on HLA-DR4 to identify rare, antigen-specific CD4+ T cells in the human T cell repertoire. They designed tetramers that could identify T cells specific for self-peptides (gp100, fibrinogen and preproinsulin) and also constructed tetramers that could identify T cells specific for viral antigens (from HIV, herpes simplex virus (HSV), cytomegalovirus (CMV) and influenza virus). Using blood from 26 healthy human donors, they found that the frequency of T cells specific for a self antigen or for a viral epitope that had not previously been encountered ranged from one to ten cells per million CD4+ T cells. Notably, there was no obvious difference between the frequencies of T cells specific for self antigens and those specific for foreign peptides. In addition, similar frequencies of HSV-specific T cells were detected in individuals who were seropositive or seronegative for HSV, suggesting that pre-exposure to a particular infection does not necessarily lead to a detectable expansion in pathogen-specific T cells.

Next, the authors examined the memory phenotype of the tetramer-positive T cells. They were surprised to find many memory-type HIV-specific, CMV-specific and HSV-specific T cells in adults who were seronegative for these viruses — on average, more than 50% of the virus-specific T cells in these individuals showed a memory phenotype. When umbilical cord blood samples were assessed by tetramer analysis, the authors found similar frequencies of HIV-specific T cells to those seen in adults. However, unlike the adult HIV-specific T cells, all of the HIV-specific T cells in the cord blood samples showed a naive phenotype. So, newborns have a full repertoire of T cells that can recognize foreign antigens but do not acquire memory-like T cells until later in life.

The authors hypothesized that exposure to cross-reactive environmental antigens may drive the development of virus-specific memory T cells in uninfected individuals. To assess this, they generated distinct HIV-1-specific clones from human donors and stimulated them with peptides from environmental antigens that have a similar sequence to T cell epitopes present in the full-length HIV-1 peptide. They found that 21% of the HIV-1-specific clones responded to at least two of the putative cross-reactive peptides. Interestingly, the sources of the cross-reactive peptides were diverse and included bacteria from the intestine and soil, and also ocean algae and plants.

Finally, to study cross-reactive T cell responses to a known antigenic challenge, the authors vaccinated two individuals with an H1N1 influenza vaccine. They cloned T cells specific for haemagglutinin from this influenza virus strain and found that these T cells could also respond to peptides derived from the bacterium Finegoldia magna and the protozoan Trichomonas vaginalis. Furthermore, they showed that influenza vaccination not only expanded memory T cells specific for the seasonal haemagglutinin variant but also promoted the development of a population of memory-type CD4+ T cells that were also specific for the F. magna-derived peptide.

The authors suggest that a lack of these cross-reactive memory T cells in very young children could partly account for their vulnerability to infectious diseases. Furthermore, their findings provide a mechanism for studies showing that vaccination has survival benefits that are independent of protection from the specific pathogen targeted by the vaccine.