The power of help: mechanistic insights into CD4⁺ T cell differentiation in vaccination and cancer

Abstract

This thesis investigates CD4⁺ T cell biology, a key component of adaptive immunity, focusing on differentiation, function, and their role in shaping immune responses in vaccination and cancer. Using a mouse DNA vaccination model, we identified a Th1/Tfh precursor state from which CD4⁺ T cells clonally differentiate into Th1 or Tfh cells. Formation of these precursors requires CD28 signaling, while differentiation to Th1 or Tfh cells depends on CD40-CD40L or ICOS-ICOSL interactions, respectively, with cDC1s and B cells mediating this process.

We show that activated CD4⁺ T cells amplify monocyte-derived dendritic cell responses, creating a feedforward loop that enhances both CD4⁺ and CD8⁺ T cell effector differentiation. Additionally, we demonstrate that CD4⁺ T cell help is critical for full CD8⁺ T cell effector differentiation derived from stem-like cells, while insufficient help leads to differentiation stop in the stem-like state, potentially contributing to T cell exhaustion. In cancer models, radiotherapy combined with immune checkpoint blockade can inadvertently promote Treg activation, dampening anti-tumor immunity; blockade of CD86 improved outcomes.

Overall, this work elucidates mechanisms regulating CD4⁺ T cell differentiation, their crosstalk with myeloid cells and CD8⁺ T cells, and highlights costimulatory pathways as potential therapeutic targets to optimize vaccination and cancer immunotherapy.