Visiting Researcher Rutgers New Jersey Med. Sch., United States
Disclosure(s):
Naoya Tatsumi, PhD: No financial relationships to disclose
Introduction/Rationale: Naïve CD4T cells differentiate into distinct T helper (Th) subsets depending on the type of dendritic cell (DC) presenting antigen. While different DC subsets are thought to present antigen to CD4T cells with distict spatiotemporal dynamics in lymph nodes (LNs), how these DC–T cell interactions are spatially and temporally organized and how they instruct Th differentiation remain incompletely understood. We previously showed that CD301b+ DCs, a major subset of migratory cDC2s, are strategically positioned near high endothelial venules at the T cell–B cell border in antigen-draining LNs. There, they engage incoming naïve polyclonal CD4T cells irrespective of the immunization context, facilitating efficient repertoire scanning and robust expansion of antigen-specific clones. Upon cognate interaction, CD301b+ cDC2s upregulate IL-2, which enhances IL-2 receptor signaling in CD4 cells to promote Th2 differentiation while suppressing the T follicular helper (Tfh) program.
Methods: To define the temporal and subset-specific contributions of DCs, we immunize mice subcutaneously with soluble OVA plus either a Th1- or Th2-polarizing adjuvant, followed by adoptive transfer of OVA-specific OT-II CD4 T cells.
Results: Here we show that OT-II cells undergo multiple waves of TCR activation during priming. The first wave, mediated by CD301b+ cDC2s shortly after LN entry, is characterized by ERK-dominant TCR signaling, leading to optimal IRF4 induction. The second wave, occurring at later stages, is primarily driven by cDC1s and marked by strong activation of proximal TCR signaling components. Functionally, depletion of CD301b+ DC abrogated Th2 differentiation without affecting Th1 development, whereas cDC1 depletion significantly impair Th1 differentiation.
Conclusion: These findings support a model in which distinct DC subsets provide non-redundant, temporally coordinated cues to antigen-specific CD4 T cells, directing Th fate specification through sequential interactions.
