Splenic Red Pulp Macrophages Cross-Prime Early Effector CTL That Provide Rapid Defense against Viral Infections

Abstract

Cross-presentation allows dendritic cells (DCs) to present peptides derived from endocytosed Ags on MHC class I molecules, which is important for activating CTL against viral infections and tumors. Type 1 classical DCs (cDC1), which depend on the transcription factor Batf3, are considered the main cross-presenting cells. In this study, we report that soluble Ags are efficiently cross-presented also by transcription factor SpiC-dependent red pulp macrophages (RPM) of the spleen. In contrast to cDC1, RPM used the mannose receptor for Ag uptake and employed the proteasome-and TAP-dependent cytosolic cross-presentation pathway, previously shown to be used in vitro by bone marrow-derived DCs. In an in vivo vaccination model, both cDC1 and RPM cross-primed CTL efficiently but with distinct kinetics. Within a few days, RPM induced very early effector CTL of a distinct phenotype (Ly6A/E + Ly6C (+) KLRG1 2 CD127 2 CX 3 CR1 2 Grz-B + ). In an adenoviral infection model, such CTL contained the early viral spread, whereas cDC1 induced short-lived effector CTL that eventually cleared the virus. RPM-induced early effector CTL also contributed to the endogenous antiviral response but not to CTL memory generation. In conclusion, RPM can contribute to antiviral immunity by generating a rapid CTL defense force that contains the virus until cDC1-induced CTL are available to eliminate it. This function can be harnessed for improving vaccination strategies aimed at inducing CTL.

Antigen Cross-Presentation by Macrophages

“…These OT-1 cells activated by the red pulp macrophages did not express activation markers CD127, KLRG1, and CX3CR1, suggesting they were so-called early effector cells, which do not develop into memory cytolytic T cells (23,24). In contrast to the cDC1 cells, uptake of the model antigen ovalbumin by the red pulp macrophages relied on the mannose receptor CD206 (23). To address the role of cross-presentation by red pulp macrophages in vivo, mice negative for the transcription factor SpiC were studied (23).…”

“…For instance, although depletion with CD11c will remove both CD11c hi CD11b + CD8α − MHCII + and CD11c hi CD11b − CD8α + MHCII + cDC subsets (22), the selection of CD11b is not sufficient to distinguish the various spleen macrophage populations because this would require selection on CD169 or SIGN-R1 + (5,22). Moreover, this isolation method might result in contamination of the CD11c + DC population with CD11c int F4/80 high red pulp macrophages (23).…”

“…In contrast to the cDC1 cells, uptake of the model antigen ovalbumin by the red pulp macrophages relied on the mannose receptor CD206 (23). To address the role of cross-presentation by red pulp macrophages in vivo, mice negative for the transcription factor SpiC were studied (23). SpiC mice lack CD11c int F4/80 high red pulp macrophages, as SpiC is required for their development, whereas cDC1 DCs are unaltered because they rely on the transcription factor Batf3 (23,25).…”

“…To address the role of cross-presentation by red pulp macrophages in vivo, mice negative for the transcription factor SpiC were studied (23). SpiC mice lack CD11c int F4/80 high red pulp macrophages, as SpiC is required for their development, whereas cDC1 DCs are unaltered because they rely on the transcription factor Batf3 (23,25). Infection of SpiC knockout OT-1 mice with AdLGO adenovirus-expressing ovalbumin resulted in a higher initial viral load, whereas viral clearance by ovalbumin-recognizing OT-I cytolytic T cells was achieved after 10 days.…”

A Newly Generated DOCK8-expressing T Follicular Helper Cell Type, aiCD4 T Cell, Causes Systemic Lupus Erythematosus: Self-Organized Criticality Theory

“…5). In the red pulp, DOCK8 + CD4 T cells could also meet the red pulp macrophages which are highly efficient at cross-presenting antigens to T cells and maturing CTLs (38) and thus important for the induction of lupus tissue injuries (24,25).…”