A potent role for memory CD8+ T cells in heterologous immunity was shown with a respiratory mucosal model of viral infection. Memory CD8+ T cells generated after lymphocytic choriomeningitis virus (LCMV) infection were functionally activated in vivo to produce interferon-gamma (IFN-gamma) during acute infection with vaccinia virus (VV). Some of these antigen-specific memory cells selectively expanded in number, which resulted in modulation of the original LCMV-specific T cell repertoire. In addition, there was an organ-selective compartmental redistribution of these LCMV-specific T cells during VV infection. The presence of these LCMV-specific memory T cells correlated with enhanced VV clearance, decreased mortality and marked changes in lung immunopathology. Thus, the participation of pre-existing memory T cells specific to unrelated agents can alter the dynamics of mucosal immunity and disease course in response to a pathogen.

Experiments designed to distinguish virus-specific from non-virus-specific T cells showed that bystander T cells underwent apoptosis and substantial attrition in the wake of a strong T-cell response. Memory CD8 T cells (CD8 ؉ CD44 hi ) were most affected. During acute viral infection, transgenic T cells that were clearly defined as non-virus specific decreased in number and showed an increase in apoptosis. Also, use of lymphocytic choriomeningitis virus (LCMV) carrier mice, which lack LCMV-specific T cells, showed a significant decline in non-virus-specific memory CD8 T cells that correlated to an increase in apoptosis in response to the proliferation of adoptively transferred virus-specific T cells. Attrition of T cells early during infection correlated with the alpha/beta interferon (IFN-␣/␤) peak, and the IFN inducer poly(I:C) caused apoptosis and attrition of CD8 ؉ CD44 hi T cells in normal mice but not in IFN-␣/␤ receptor-deficient mice. Apoptotic attrition of bystander T cells may make room for the antigen-specific expansion of T cells during infection and may, in part, account for the loss of T-cell memory that occurs when the host undergoes subsequent infections.

CD8 T cell cross-reactivity between viruses can play roles in protective heterologous immunity and damaging immunopathology. This cross-reactivity is sometimes predictable, such as between lymphocytic choriomeningitis virus (LCMV) and Pichinde virus, where cross-reactive epitopes share six out of eight amino acids. Here, however, we demonstrate more subtle and less predictable cross-reactivity between LCMV and the unrelated vaccinia virus (VV). Epitope-specific T cell receptor usage differed between individual LCMV-infected C57BL/6 mice, even though the mice had similar epitope-specific T cell hierarchies. LCMV-immune mice challenged with VV showed variations, albeit in a distinct hierarchy, in proliferative expansions of and down-regulation of IL-7Rα by T cells specific to different LCMV epitopes. T cell responses to a VV-encoded epitope that is cross-reactive with LCMV fluctuated greatly in VV-infected LCMV-immune mice. Adoptive transfers of splenocytes from individual LCMV-immune donors resulted in nearly identical VV-induced responses in each of several recipients, but responses differed depending on the donor. This indicates that the specificities of T cell responses that are not shared between individuals may influence cross-reactivity with other antigens and play roles in heterologous immunity upon encounter with another pathogen. This variability in cross-reactive T cell expansion that is unique to the individual may underlie variation in the pathogenesis of infectious diseases.

Having previously shown that previous immunity to one virus can influence the host response to a subsequent unrelated virus, we questioned whether the outcome to a given virus infection would be altered in similar or different ways by previous immunity to different viruses, and whether immunity to a given virus would have similar effects on all subsequent infections. In mouse models of respiratory viral infections, immunity to lymphocytic choriomeningitis virus (LCMV), murine cytomegalovirus (MCMV), or influenza A virus enhanced both Th1-type cytokine responses and viral clearance in the lung on vaccinia virus infection. A common pathological feature was the presence of chronic mononuclear infiltrates instead of the acute polymorphonuclear response seen in the infected nonimmune mice, but some pathologies such as enhanced bronchus-associated lymphoid tissue and bronchiolitis obliterans were unique for the immunizing virus, LCMV. Immunity to influenza virus influenced subsequent infections diversely, inhibiting vaccinia virus but enhancing LCMV and MCMV titers and completely altering cytokine profiles. Influenza virus immunity enhanced the mild mononuclear responses usually observed during acute infections with MCMV or LCMV in nonimmune mice, but unique features such as enhanced bronchiolization and mononuclear consolidation occurred during MCMV infection of influenza virus-immune mice. Heterologous immunity induced two patterns of disease outcome dependent on the specific virus infection sequence: improved, if the acute response switched from a neutrophilic to a lymphocytic response or worsened, if it switched from a mild to a severe lymphocytic response. Heterologous immunity thus occurs between many viruses, resulting in altered protective immunity and lung immunopathology, and this is influenced by the specific virus infection sequence.

CD8 T cells persist at high frequencies in peripheral organs after resolution of an immune response, and their presence in the periphery is important for resistance to secondary challenge. We show here that LCMV-specific T cells in peripheral tissue (peritoneal cavity, lung, fat pads) reacted much less with the apoptotic marker Annexin-V than those in spleen and lymph nodes. This was not due to a TCR-based selection. In comparison to lymphoid tissue, T cells in the periphery expressed lower levels of Fas and Fas ligand and were resistant to activation-induced cell death in vitro. This may contribute to the survival of nondividing peripheral memory T cells, enabling them to efficiently function without being driven into apoptosis.