Profound lymphopenia has been observed during many acute viral infections, and our laboratory has previously documented a type I IFN-dependent loss of CD8 T cells immediately preceding the development of the antiviral T cell response. Most memory (CD44high) and some naive (CD44low) CD8 T cells are susceptible to IFN-induced attrition, and we show in this study that the IFN-induced attrition of CD8+CD44high T cells is associated with elevated activation of caspase-3 and caspase-8. We questioned whether TCR engagement by Ag would render CD8 T cells resistant to attrition. We tested whether a high concentration of Ag (GP33 peptide) would protect lymphocytic choriomeningitis (LCMV)-specific naive CD8 T cells (TCR transgenic P14 cells specific for the GP33 epitope of LCMV) and memory CD8 T cells (GP33-specific LCMV-immune cells) from depletion. Both naive P14 and memory GP33-specific donor CD8 T cells decreased substantially 16 h after inoculation with the Toll receptor agonist and IFN inducer, poly(I:C), regardless of whether a high concentration of GP33 peptide was administered to host mice beforehand. Moreover, donor naive P14 and LCMV-specific memory cells were depleted from day 2 LCMV-infected hosts by 16 h posttransfer. These results indicate that Ag engagement does not protect CD8 T cells from the IFN-induced T cell attrition associated with viral infections. In addition, computer models indicated that early depletion of memory T cells may allow for the generation for a more diverse T cell response to infection by reducing the immunodomination caused by cross-reactive T cells.

Virus-specific memory T cell populations demonstrate plasticity in antigen recognition and in their ability to accommodate new memory T cell populations. The degeneracy of T cell antigen recognition and the flexibility of diverse antigen-specific repertoires allow the host to respond to a multitude of pathogens while accommodating these numerous large memory pools in a finite immune system. These cross-reactive memory T cells can be employed in immune responses and mediate protective immunity, but they can also induce life-threatening immunopathology or impede transplantation tolerance and graft survival. Here we discuss examples of altered viral pathogenesis occurring as a consequence of heterologous T cell immunity and propose models for the maintenance of a dynamic pool of memory cells.

Why some virus-specific CD8 TCR repertoires are diverse and others restricted or "oligoclonal" has been unknown. We show here that oligoclonality and extreme clonal dominance can be a consequence of T cell cross-reactivity. Lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PV) encode NP(205-212) epitopes that induce different but highly cross-reactive diverse TCR repertoires. Homologous viral challenge of immune mice only slightly skewed the repertoire and enriched for predictable TCR motifs. However, heterologous viral challenge resulted in a narrow oligoclonal repertoire with dominant clones with unpredictable TCR sequences. This shift in clonal dominance varied with the private, i.e., unique, specificity of the host's TCR repertoire and was simulated using affinity-based computer models. The skewing differences in TCR repertoire following homologous versus heterologous challenge were observed within the same private immune system in mice adoptively reconstituted with memory CD8 T cell pools from the same donor. Conditions driving oligoclonality resulted in an LCMV epitope escape variant in vivo resembling the natural Lassa virus sequence. Thus, T cell oligoclonality, including extremes in clonal dominance, may be a consequence of heterologous immunity and lead to viral escape. This has implications for the design of peptide-based vaccines, which might unintentionally prime for skewed TCR responses to cross-reactive epitopes.

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Viruses can cause a severe lymphopenia early in infection and a subsequent, lasting loss of pre-existing CD8+ memory T cells. We therefore questioned how well virus Ag-specific memory CD8+ T cells could reconstitute mice rendered lymphopenic as a consequence of genetics, irradiation, or viral or poly(I:C)-induced cytokines. In each case, reconstitution of the CD8+ compartment was associated with limited division of virus-specific memory T cells and a reduction in their proportion. This indicates that foreign Ag-experienced CD44highCD8+ memory T cells may respond differently to homeostatic signals than other CD44highCD8+ cells, and that events inducing lymphopenia may lead to a permanent reduction in T cell memory.