Batf3 transcription factor‐dependent DC subsets in murine CMV infection: Differential impact on T‐cell priming and memory inflation

Abstract

Priming of CD81 T cells specific for viruses that interfere with the MHC class I presentation pathway is a challenge for the immune system and is believed to rely on cross-presentation. Cytomegalovirus (CMV) infection induces vigorous CD8 1 T-cell responses despite its potent immune evasion strategies. Furthermore, CD8 1 T cells specific for a subset of viral epitopes accumulate and are maintained at high levels exhibiting an activated phenotype -referred to as ''inflationary T cells''. Taking advantage Batf3 À/À mice in which the development of cross-presenting CD8a 1 and CD103 1 DCs is severely compromised, we analyzed their role in the induction and inflation of murine (M)CMV-specific CD8 1 T-cell responses. We found that priming of MCMV-specific CD8 1 T cells was severely impaired in the absence of cross-presenting DCs. However, inflation of two immuno-dominant MCMVspecific CD8 1 T-cell populations was largely normal in the absence of cross-presenting DCs, indicating that inflation during latency was mainly dependent on direct antigen presentation. These results highlight differential antigen presentation requirements during acute and latent MCMV infection.

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

“…Our finding corroborates and extends the results of two other recently published studies. Torti et al (55) showed that priming of MCMV-specific CD8 + T cells was severely impaired in Batf3 knockout mice, which are compromised in the development of CD8a + and CD103 + DC subsets. This pointed to a prominent role for cross-presentation, but left open whether the residual T cell priming observed resulted from direct priming or from other remaining APCs in these mice that are capable of cross-presentation.…”

“…A previous study suggested that differentiation of T cells primed early in infection, as well as de novo priming of naive T cells during chronic infection, contribute to the expansion and maintenance of certain effector memory T cells at high levels (79). Recent results indicated moreover that cells of nonhematopoietic origin are involved in this process (55,80,81). We hypothesized, therefore, that stochastic expression of the major immediate early promoter-driven reporter genes by latently infected host cells may also give rise to T cells recognizing the signal peptide-encoded epitopes.…”

“…55 49 -specific T cells were generated by E7 49 peptide restimulation of splenocytes from DvRAP noX NP immunized mice, and NP 366 -specific T cells were isolated from the spleen of a naive F5 TCRtransgenic mouse (72) using a negative selection CD8 T cell kit (Miltenyi). Stroma target cells, generated from LNs of naive B6 mice, were either loaded with peptides or infected with recombinant viruses and cocultivated with the specific T cells for 18 h to quantify IFN-g-producing cells by an ELISPOT assay (eBioscience) according to the manufacturer's instructions.…”

“…Two recent studies that relied on a replication-defective MCMV mutant or on a mouse strain with an impaired ability for crosspresentation (54,55) provided evidence that priming occurs mainly by cross-presentation. If cross-presentation prevails, a bias in the antiviral T cell response is expected, because cross-presentation favors Ag with certain characteristics (56)(57)(58)(59)(60), one being the stability of an antigenic protein (61).…”

Acquisition of MHC:Peptide Complexes by Dendritic Cells Contributes to the Generation of Antiviral CD8+ T Cell Immunity In Vivo

“…5B). Although we cannot entirely exclude a residual cross-presentation capacity of other DC (34) or macrophage subsets (35) in the Batf3 null mice, this contribution to Ag presentation has been reported to be inefficient in this setting (17,36). When taken together with the OT-1 CD8 + T cell priming observed by our adoptive DC transfer system in the K bm1 mouse (Fig.…”