No one is naive: the significance of heterologous T-cell immunity

Abstract

Memory T cells that are specific for one virus can become activated during infection with an unrelated heterologous virus, and might have roles in protective immunity and immunopathology. The course of each infection is influenced by the T-cell memory pool that has been laid down by a host's history of previous infections, and with each successive infection, T-cell memory to previously encountered agents is modified. Here, we discuss evidence from studies in mice and humans that shows the importance of this phenomenon in determining the outcome of infection.

A stochastic model of cytotoxic T cell responses

“…T cells divide for about 5 days (Lehmann-Grube, 1988), which implies that a single na. ıve T cell can generate 60,000 effector cells, which agrees with experiment (Welsh and Selin, 2002). If we assume that a T cell cannot divide more than 100 times, there could to be up to 3100 subpopulations of effector cells per T cell clone, or 100 A phase subpopulations and 3000 B phase subpopulations.…”

“…These clones have affinities not only for the epitope in question, but for all possible epitopes. In a system subjected to heterologous infections, memory cells that cross-react to multiple antigens might be an essential part of our immune responses (Welsh and Selin, 2002). Our digit string implementation, which implicitly defines an affinity between a TCR and any epitope, allows us to model the effect of infections over an organism's lifetime.…”

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

“…It is intriguing to speculate that TV9 may be a cross-reactive determinant that HIV-1 shares with a heterologous organism(s) (87). Thus, variability in cross-reactive T cell expansion unique to an individual may influence the character of the TV9-specific response on encountering HIV-1.…”

Vaccination and heterologous immunity: educating the immune system

“…When LCMV-immune male mice are infected with VACV intraperitoneally there is a substantial reduction in VACV titer; however, some of these mice develop severe panniculitis, in the form of inflammation and necrosis of visceral fat tissue. 22,30,33 This type of abdominal fat pathology is seen in human syndromes of unknown etiology, such as WeberChristian disease or lupus erythematosis, and erythema nodosum, a more benign and more common form of panniculitis, involves inflammation of subcutaneous fat tissue sometimes seen after vaccinations with VACV, human papilloma virus (HPV) and HBV. 30,[70][71][72][73] When LCMV-immune mice are infected intranasally with VACV, there is again a reduction of viral titers in the A. Gil et al…”

“…The mechanisms of heterologous immunity can vary, but the focus of this review is on experimental systems where both beneficial and detrimental heterologous immunity are mediated by crossreactive T cells. 22,23 More than 20 years of research have delineated basic principles of heterologous immunity, such as (1) T cell crossreactivity is quite common between unrelated pathogens and alters T cell immunodominance; 24 (2) networks of crossreactive T cells alter the efficacy of the T cell response and influence protective immunity and immunopathology; [25][26][27][28][29][30] (3) T cell crossreactivity can lead to narrowing of the T cell repertoire and generation of viral escape mutants; 31 (4) the private specificity of crossreactive T cells can determine an individual's disease outcome in regards to protective immunity and immunopathology; [31][32][33] (5) heterologous immunity can reduce the effectiveness of vaccines due to immunodominant skewing of undesired T cell responses; 29,34 (6) peptide-dependent interventions or cytokine Transactions of the Royal Society of Tropical Medicine and Hygiene blocking therapy can be used to prevent severe pathology caused by heterologous immunity; 25,30,34 and (7) the immune response to each new pathogen impacts the frequencies, distributions and activities of memory T cells to previous infections. 22,35,36 The contention is that heterologous immunity is the norm, not the exception, but given the diversity in human genetics, MHC and infection histories, is it too complicated an issue to address?…”