The Role of Antigen in the Localization of Naive, Acutely Activated, and Memory CD8+ T Cells to the Lung During Influenza Pneumonia

Abstract

The role of Ag in the recruitment and localization of naive, acutely activated, and memory CD8+ T cells to the lung during influenza infection was explored using TCR-transgenic (Tg) mice. Naive, Thy1.2+CD8+ OT-I TCR-Tg cells were primed and recruited to the lung after transfer into congenic Thy1.1+ recipients challenged with a genetically engineered influenza virus (influenza A/WSN/33 (WSN)-OVAI) containing the Kb restricted OVA257–264 epitope (siinfekl) in the viral neuraminidase stalk. However, if the transferred animals were infected with a similar influenza virus that expressed an irrelevant Kb epitope (WSN-PEPII), no TCR-Tg T cells were detectable in the lung, although they were easily visible in the lymphoid organs. Conversely, there were substantial numbers of OT-I cells found in the lungs of WSN-PEPII-infected mice when the animals had been previously, or were concurrently, infected with a recombinant vaccinia virus expressing OVA. Similar results were obtained with nontransgenic populations of memory CD8+ T cells reactive to a murine γ-herpesvirus-68 Ag. Interestingly, the primary host response to the immunodominant influenza nucleoprotein epitope was not affected by the presence of memory or recently activated OT-I T cells. Thus, although Ag is required to activate the T cells, the subsequent localization of T cells to the lung during a virus infection is a property of recently activated and memory T cells and is not necessarily driven by Ag in the lung.

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

“…We believe the cells are lost by apoptosis or phagocytosis, because previous studies have shown that lung airway memory T cells are unable to migrate from the lung airways back into the circulation (7,37). These observations extend previous studies in the field by distinguishing the relative contributions of resident memory cells, recruitment, and proliferation to the expansion of memory cells in the lung airways induced by heterologous virus infections (14,19).…”

“…Recent studies have shown that respiratory virus infections induce an increase in the numbers of heterologous memory CD8 ϩ T cells in the lung or lung airways (14,19,28). However, it was not clear whether this reflected local proliferation or recruitment of cells from other sites.…”

“…Two recent studies (14,19) have indicated that secondary pulmonary infection results in a change in the absolute numbers of memory T cells in the lung or lung airways, but it was not clear whether this reflected local proliferation or recruitment of cells from other sites. In addition, the specific impact of heterologous infection on the effector/memory populations already resident in the lung airways was not assessed.…”

Frequency, Specificity, and Sites of Expansion of CD8+ T Cells during Primary Pulmonary Influenza Virus Infection

“…Indeed, Ag-nonspecific memory CD8 ϩ T cells have been shown to migrate to the lungs after respiratory infection with RSV, influenza virus, and Sendai virus (33)(34)(35). However, nonspecific recruitment of irrelevant memory CD8 ϩ T cells to the inflamed lungs is an unlikely explanation for our findings.…”

Unique Ability of Activated CD4+ T Cells but Not Rested Effectors to Migrate to Non-lymphoid Sites in the Absence of Inflammation

“…Non-lymphoid Sites following Adoptive Transfer-Our laboratory (6) as well as others (7,10,11,14,18) have demonstrated that T cell effectors activated by infection or antigen in adjuvant can migrate to the site of inflammation where they secrete cytokines, display cytolytic activity, and participate in pathogen clearance. To analyze the regulation of CD4 ϩ T cell subset recruitment to non-lymphoid sites, we used a standard in vitro activation protocol to generate Th1 and Th2 effector cells that produced interferon-␥ and IL-4, respectively (15,17,19).…”