Priming of CD8+ T Cells against Cytomegalovirus-Encoded Antigens Is Dominated by Cross-Presentation

Abstract

CMV can infect dendritic cells (DCs), and direct Ag presentation could, therefore, lead to the priming of CMV-specific CD8+ T cells. However, CMV-encoded immune evasins severely impair Ag presentation in the MHC class I pathway; thus, it is widely assumed that cross-presentation drives the priming of antiviral T cells. We assessed the contribution of direct versus cross priming in mouse CMV (MCMV) infection using recombinant viruses. DCs infected with an MCMV strain encoding the gB498 epitope from HSV-1 were unable to stimulate in vitro naive gB498-specific CD8+ T cells from TCR transgenic mice. Infection of C57BL/6 mice with this recombinant virus led, however, to the generation of abundant numbers of gB498-specific T cells in vivo. Of the DC subsets isolated from infected mice, only CD8α+ DCs were able to stimulate naive T cells, suggesting that this DC subset cross-presents MCMV-encoded Ag in vivo. Upon infection of mice with MCMV mutants encoding Ag that can either be well or hardly cross-presented, mainly CD8+ T cells specific for cross-presented epitopes were generated. Moreover, even in the absence of immune evasion genes interfering with MHC class I–mediated Ag presentation, priming of T cells to Ag that can only be presented directly was not observed. We conclude that the host uses mainly DCs capable of cross-presentation to induce the CMV-specific CD8+ T cell response during primary, acute infection and discuss the implications for the development of a CMV vaccine.

Cooperation between Epstein-Barr Virus Immune Evasion Proteins Spreads Protection from CD8+ T Cell Recognition across All Three Phases of the Lytic Cycle

“…Understanding that endogenous antigen presentation in lytically infected B cells is the predominant source of stimulation for CD8 + T cell responses to lytic cycle antigens, as opposed to cross-presentation via dendritic cells as is common for other herpesviruses such CMV [41]–[43], places greater importance on the role of the phase-specific interference of antigen presentation identified in the present work. In this context our new data implicate a significant contribution of BILF1 to the pattern of immunodominance that is seen for EBV.…”

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

“…164,165 Due to the importance of this process several respiratory viruses, including hRSV 27 and hMPV 26 have evolved different mechanisms to impair T cell activation. Indeed, both of these viruses impair the T cell response, causing, at least in part, an aberrant adaptive immune response and poor immunological memory against hRSV 71,166 and hMPV.…”

The (gradual) rise of memory inflation

“…It is less evident whether non‐hemopoeitic cells can be really sufficient for priming although clearly for maximal early priming cross‐presenting DCs are involved79 and these cells can additionally prime the conventional (non‐inflationary) memory populations in parallel. Some debate still exists as to the nature of the non‐hemopoetic cell required.…”