DCs at the center of help: Origins and evolution of the three-cell-type hypothesis

Abstract

Last year was the 10th anniversary of Ralph Steinman's Nobel Prize awarded for his discovery of dendritic cells (DCs), while next year brings the 50th anniversary of that discovery. Current models of anti-viral and anti-tumor immunity rest solidly on Steinman's discovery of DCs, but also rely on two seemingly unrelated phenomena, also reported in the mid-1970s: the discoveries of "help" for cytolytic T cell responses by Cantor and Boyse in 1974 and "cross-priming" by Bevan in 1976. Decades of subsequent work, controversy, and conceptual changes have gradually merged these three discoveries into current models of cell-mediated immunity against viruses and tumors.

Figure 1.

A developing scheme for CD4 T cell–mediated help for CTL responses. The cDC1 subset of cDCs can serve as an autonomous platform for priming both CD4 and CD8 T cells. The cDC1 captures and process cell-associated antigens for presentation by MHC-II molecules and cross-presentation (XP) for MHC-I molecules. CD4 T cell engagement induces surface expression of its CD40 ligand, stimulating CD40 signaling in cDC1 cells. This signaling enhances priming of CD8 T cells through mechanisms that remain incompletely defined, including induction of CD70 and potentially other costimulatory ligands, as well as DC-intrinsic effects.

Figure 2.

Cross-priming for a secondary cytotoxic response to minor H antigens. Splenocytes from B10.D2 mice were used to immunize F1 (BALB/c x BALB.B) mice to induce CTL specific for minor H-2 antigens differing between the B10 and BALB/c backgrounds. After in vivo priming, lymphocytes from immunized F1 mice were boosted in vitro against irradiated splenocytes from F1 (BALB/c x BALB.B) mice, B10.D2 mice, B10 mice, or an equal mixture of splenocytes from B10.D2 and B10 mice. CTL activity was then assayed against target cells from B10.D2 or B10 mice. Cytolysis of B10.D2 targets is consistent with priming by direction of the immunizing B10.D2 cell and does not require an explanation by cross-presentation. In contrast, cytolysis of B10 targets cannot be explained by direct priming by the immunizing cells, suggesting that minor antigens from the B10 background were recognized in vivo by CTLs in the context of the host H-2^b allele. This was cross-priming. Adapted from Bevan (1976).

Figure 3.

Linked recognition of helper activity is required for the in vivo generation of cytotoxic T lymphocytes. A congenic pair of B6 mice were generated differing only at the Qa-1 locus. Original B6 mice express the Qa-1^b allele, while the B6.Tla^a congenic partner expresses the Qa-1a^a allele. Immunization of female B6.Tla^a mice with splenocytes from B6 female mice fails to induce a Qa-1^b specific CTL response. In contrast, immunization using splenocytes from B-6 male does generate the Qa-1b specific CTL. Male cells carry the additional H-Y antigen that serves as a helper determinant. The requirement for linked recognition was indicated by the inability to generate CTLs using a mixed immunization with B6 female splenocytes and male B6.Tla^a splenocytes. This suggested that the H-Y helper determinant and Qa-1^b CTL determinant need to be presented on the same cell. Adapted from Keene and Forman (1982).