Evaluation of Immunological Paradigms in a Virus Model: Are Dendritic Cells Critical for Antiviral Immunity and Viral Clearance?

Abstract

We have examined the role of dendritic cells (DCs) in the antiviral immune response and viral clearance using a transgenic mouse model (CD11c-diphtheria toxin (DT) receptor GFP) that allows for their conditional ablation in vivo. DT administration systemically ablated conventional and IFN-producing plasmacytoid DCs (pDCs) in transgenic, but not nontransgenic littermates, without elimination of splenic macrophages. Unexpectedly, early (12 and 48 h postinfection) viral clearance of vesicular stomatitis virus was normal in DC-depleted mice despite markedly reduced serum titers of type I IFN. DC-depleted mice remained virus-free with the exception of a subset (∼30%) that developed overwhelming and fatal brain infections 6 days postinfection. However, DT treatment profoundly inhibited clonal expansion of naive CD8+ vesicular stomatitis virus-specific T cells without altering the primary Th1 and Th2 cytokine response. Optimal clonal expansion required pDCs because selective elimination of these cells in vivo with a depleting Ab also suppressed expansion of tetramer+ cells, although Th1/Th2 cytokine production remained unaltered. Collectively, these data indicate that conventional DCs and to a lesser extent pDCs are critical for proliferation of naive antiviral T cells. However, other components of the primary adaptive immune response (Th1/Th2 cytokines) are essentially normal in the absence of DCs, which may account for the efficient viral clearance seen in DC-depleted mice. Thus, sufficient redundancy exists in the immune system to sustain efficient viral clearance despite loss of an APC considered essential for induction of a primary antiviral immune response.

Persistent Antigen Presentation after Acute Vesicular Stomatitis Virus Infection

“…Whether VSV proteins were produced in these scenarios was not determined. Our data favor the hypothesis that in the apparent absence of infectious virus (6,45), low-level translation of VSV mRNA occurs, resulting in production of protein and subsequent antigen expression.…”

“…1A and B). Thus, virus-encoded antigen remained several days after VSV has been reported to be cleared from infected mice (6). Even more surprising was the demonstration that antigen could be detected by adoptively transferred CD8 T cells transferred 22, 31, or 45 days after VSV infection.…”

Probing in vivo dendritic cell functions by conditional cell ablation

“…Viruses cDC requirement for LCMV, 35 HSV-1, 36 VSV, 37 influenza, 38 CTL response cDC independence of anti-VSV B and CD4 T-cell response 36,39 Bacteria cDC requirement for anti-Listeria CTL response 11,40 cDC requirement for efficient Mycobacterium tuberculosis CD4 T-cell response 41 cDC requirement for anti-Salmonella response 42,43 cDC independence of UPEC clearance 44 Parasites cDC requirement for anti-Plasmodium 11 and anti-Leishmania response 45,46 Prions cDC requirement for intestinal Scrapie agent neuroinvasion 47 Miscellaneous Tolerance cDC role in Ig complex-mediated priming and tolerization 48,49 cDC independence of peripheral CD4 T-cell tolerization 50 NK responses cDC requirement for NK cell activation by IL-15 trans-presentation 25 NKT responses cDC requirement for glycolipid presentation 51,52 CTL responses cDC requirement for efficient CTL memory generation 27 Respiratory tract cDC requirement for asthma and experimental allergic rhinitis 18,53 Tumor studies cDC requirement for antitumor immunity 52 DC functions by conditional cell ablation A Sapoznikov and S Jung subpopulations and generally provided by non-hematopoietic cells, including stromal and follicular dendritic cells; 58 and (2) the chemokine macrophage migration inhibitory factor (MIF) that controls mature B-and tumor cell survival through triggering of the CD74-CD44 receptor complex. [59][60][61] 70 on pDC.…”

Antigen Presentation by Nonhemopoietic Cells Amplifies Clonal Expansion of Effector CD8 T Cells in a Pathogen-Specific Manner

“…Several studies have assessed the role of hemopoietic cells in initiating CD8 T cell responses, either by removing the restricting MHC on radiation-sensitive bone marrow-derived cells or by targeted depletion of CD11c-positive cells (5)(6)(7)(8)(9)(10)(25)(26)(27). These studies unanimously show that hemopoietic cells, especially CD11c-positive cells, are needed for optimal generation of detectable CD8 T cell responses both during immunization with model Ags as well as during infection with various pathogens, including VV, VSV, LCMV, Lm, and influenza A virus, although there was some confusion with reference to LCMV (see discussion in later sections).…”