Activated Antigen-Specific CD8+ T Cells Persist in the Lungs Following Recovery from Respiratory Virus Infections

Abstract

The poor correlation between cellular immunity to respiratory virus infections and the numbers of memory CD8+ T cells in the secondary lymphoid organs suggests that there may be additional reservoirs of T cell memory to this class of infection. Here we identify a substantial population of Ag-specific T cells in the lung that persist for several months after recovery from an influenza or Sendai virus infection. These cells are present in high numbers in both the airways and lung parenchyma and can be distinguished from memory cell populations in the spleen and peripheral lymph nodes in terms of the relative frequencies among CD8+ T cells, activation status, and kinetics of persistence. In addition, these cells are functional in terms of their ability to proliferate, express cytolytic activity, and secrete cytokines, although they do not express constitutive cytolytic activity. Adoptive transfer experiments demonstrated that the long-term establishment of activated T cells in the lung did not require infection in the lung by a pathogen carrying the inducing Ag. The kinetics of persistence of Ag-specific CD8+ T cells in the lung suggests that they play a key role in protective cellular immunity to respiratory virus infections.

Nonspecific Recruitment of Memory CD8+ T Cells to the Lung Airways During Respiratory Virus Infections

“…These cells comprised ϳ70% of all CD8 ϩ T cells in the lung airways at this time ( Fig. 1A), consistent with previous studies (7). Following infection with influenza virus, the numbers of Sen-NP 324 -332 /K b -specific T cells in the lung airways increased dramatically over the first 4 days to ϳ270,000 cells (representing a Ͼ5-fold increase in cell number).…”

“…As shown in Fig. 1, (day 0, A and B), C57BL/6 mice that had recovered from a prior Sendai virus infection had substantial numbers of effector/memory cells specific for the immunodominant Sen-NP 324 -332 /K b epitope in the lung airways (ϳ50,000 cells/mouse) (7,29,30). These cells comprised ϳ70% of all CD8 ϩ T cells in the lung airways at this time ( Fig.…”

“…Similar to memory CD8 ϩ T cells in secondary lymphoid organs, memory cells in the lung airways are small resting cells (9). However, they are phenotypically distinct from memory T cells in secondary lymphoid organs in that they express acute activation markers and have reduced CD11a expression (4,7,10). Based on their activated phenotype, memory T cells in peripheral sites are frequently referred to as effector/ memory T cells (11).…”

“…Recently, it has emerged that CD8 ϩ memory T cells also persist in nonlymphoid peripheral tissues, such as the lungs, kidneys, and liver (4 -6). For example, studies in the Sendai virus system have demonstrated that substantial numbers of memory CD8 ϩ T cells, specific for the immunodominant Sendai virus nucleoprotein (Sen-NP) 3 epitope Sen-NP 324 -332 /K b , persist in the lung airways of mice that have recovered from acute infection (7,8). Similar to memory CD8 ϩ T cells in secondary lymphoid organs, memory cells in the lung airways are small resting cells (9).…”

Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung

“…Influenza A virus strains HK-ϫ31 (ϫ31; H3N2) and PR8/34 (PR8; H1N1) were prepared, titered, and stored, as described previously (34,35). For primary infection, mice were anesthetized by i.p.…”