CD4+ T-cell help delivery to monocyte-derived dendritic cells promotes effector differentiation of helper and cytotoxic T cells

Immunology Letters, vol. 275, pp. 107022

Abstract

• CD4 + T-cell activation amplifies the MoDC response in vaccine-draining lymph nodes (dLNs). • CD4 + T cells optimize the MoDC response in dLNs via CD40L and IFNγ. • CD4 + T-cell activation improves the activation and costimulatory state of monocyte-derived cells. • CD4 + T cells engage MoDCs in a feed-forward loop to improve CD4 + and CD8 + T-cell effector differentiation. Delivery of CD4 + T-cell help optimizes CD8 + T-cell effector and memory responses via CD40-mediated licensing of conventional dendritic cells (DCs). Using comparative vaccination settings that prime CD8 + T cells in presence or absence of CD4 + T-cell help, we observed that CD4 + T-cell activation promoted influx of monocytes into the vaccine-draining lymph nodes (dLNs), where they differentiated into monocyte-derived (Mo)DCs, as defined by the most recent standards. Abrogation of these responses by CCR2-targeted depletion indicated that monocyte-derived cells in the dLN promoted T-helper 1 (Th1) type effector differentiation of CD4 + T cells, as well as effector differentiation of CD8 + T cells. Monocyte-derived cells in dLNs upregulated CD40, CD80 and PD-L1 as a result of CD4 + T-cell help. The response of monocyte-derived cells to CD4 + T-cell help was independent of natural killer (NK) cells and proceeded via CD40 ligand (L)-CD40 interactions and IFNγ signaling. Our data argue for a scenario wherein activated CD4 + T cells in dLNs crosstalk via CD40L and IFNγ signals to monocytes, promoting their local differentiation into MoDCs. This event enhances formation of CD4 + Th1 and CD8 + cytotoxic effector T cell pool, most likely by virtue of their improved costimulatory status and cytokine production.

Authors 7

1. Douwe M. T. Bosma Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands

2. Julia Busselaar Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands

3. Mo D. Staal Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands

4. Elselien Frijlink Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands

5. Matthias Mack

   University Hospital Regensburg

   Affiliation as printed

   Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany

6. Fiamma Salerno Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands

7. Jannie G. Borst corresponding Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: j.g.borst@lumc.nl