Antigen persistence and the control of local T cell memory by migrant respiratory dendritic cells after acute virus infection

Abstract

Acute viral infections induce robust adaptive immune responses resulting in virus clearance. Recent evidence suggests that there may be depots of viral antigen that persist in draining lymph nodes (DLNs) after virus clearance and could, therefore, affect the adaptive immune response and memory T cell formation. The nature of these residual antigen depots, the mechanism of antigen persistence, and the impact of the persistent antigen on memory T cells remain ill defined. Using a mouse model of influenza virus infection of the respiratory tract, we identified respiratory dendritic cells (RDCs) as essential for both sampling and presenting residual viral antigen. RDCs in the previously infected lung capture residual viral antigen deposited in an irradiation-resistant cell type. RDCs then transport the viral antigen to the LNs draining the site of infection, where they present the antigen to T cells. Lastly, we document preferential localization of memory T cells to the DLNs after virus clearance as a consequence of presentation of residual viral antigen by the migrant RDC.

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

“…It is thus tempting to speculate that the capability of CD8 + T cells to respond to a short Ag pulse might reflect transient viral gene transcription and its preferred feeding of the class I pathway. The fact that CD4 + T cells respond much longer to residual Ag following viral clearance than CD8 + T cells do also indicates that antiviral CD8 + T cell responses depend on viral transcription (79,80).…”

Dendritic cells sequester antigenic epitopes for prolonged periods in the absence of antigen-encoding genetic information

“…It has been reasonably assumed that the genetic information of the virus is somehow preserved in the host, and its continued expression at a low level is responsible for this persistence. Indeed, viral transcripts have now been detected long after the virus has been cleared; nonetheless, the antigen appears to persist immunologically even longer after such transcripts cease to be detectable (8). Thus, the molecular basis of antigen persistence has remained mysterious.…”

“…This is true for chronically infecting viruses, such as the respiratory syncytial (1,2) and Sendai viruses (3), as well as lytic influenza viruses (4)(5)(6)(7)(8). The evidence that antigens persist comes from immunologic rather than biochemical studies: typically, it has been shown by the ability of the host, which has cleared the infection and in which no antigen is detectable, to readily support stimulation of adoptively transferred naïve T cells for weeks after the infection has been cleared.…”

“…An understanding of the mechanisms of antigen persistence can shed light on several significant immunologic processes: persistence of high levels of viral antigen has been implicated in compromised immune responses to chronic infections. Additionally, antigen persistence has been linked with the nature of T-cell memory elicited in response to infection (4)(5)(6)(7)(8)(9).…”

“…Indeed, viral transcripts have been detected long after the virus has been cleared; nonetheless, the antigen appears to persist immunologically significantly even longer after such transcripts cease to be detectable (8). Although the idea that antigen persistence is accounted for by undetectable levels of viral DNA or RNA is plausible, it is intellectually unsatisfactory.…”