Unappreciated complexity in T cell help for dendritic cells

CD40 has long been known as a co-stimulatory molecule involved in T cell help for dendritic cells, and thereby as a contributor to CD8⁺ T cell immunity against cancers and infections. However, CD40 signaling drives complex functional responses that can contribute to tumor-specific CD8⁺ T cell responses in unexpected ways.

Wu et al. sorted CD40^hi migratory cDC1s from skin-draining lymph nodes, stimulated these cells in vitro via CD40 and observed increased transcription of several genes, including those encoding CD70, 4-1BB, COX-2 and BCL-XL³. CD40 stimulation of bone-marrow-derived cDC1s combined with activation by polyinosinic:polycytidylic acid induced comparable gene expression patterns. To test the function of these molecules in the context of DC–CD8⁺ T cell interactions, the authors inoculated mice with immunogenic fibrosarcoma cells that can be rejected by helper-dependent CD8⁺ T cell responses⁴. Given the broad expression of some of these molecules, the authors also generated several new mouse lines in which CD70, 4-1BB, COX2 and BCL-XL were selectively missing from cDC1s and compared their response to wild-type mice and mice lacking CD40 specifically from cDC1s (Xcr1^Cre × Cd40^fl, referred to as CD40^cKO).

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