Naive CD4 T cell responses, especially their ability to help B cell responses, become compromised with aging. We find that using APC pretreated ex vivo with TLR agonists, polyinosinic-polycytidylic acid and CpG, to prime naive CD4 T cells in vivo, restores their ability to expand and become germinal center T follicular helpers and enhances B cell IgG Ab production. Enhanced helper responses are dependent on IL-6 production by the activated APC. Aged naive CD4 T cells respond suboptimally to IL-6 compared with young cells, such that higher doses are required to induce comparable signaling. Preactivating APC overcomes this deficiency. Responses of young CD4 T cells are also enhanced by preactivating APC with similar effects but with only partial IL-6 dependency. Strikingly, introducing just the activated APC into aged mice significantly enhances otherwise compromised Ab production to inactivated influenza vaccine. These findings reveal a central role for the production of IL-6 by APC during initial cognate interactions in the generation of effective CD4 T cell help, which becomes greater with age. Without APC activation, aging CD4 T cell responses shift toward IL-6–independent Th1 and CD4 cytotoxic Th cell responses. Thus, strategies that specifically activate and provide Ag to APC could potentially enhance Ab-mediated protection in vaccine responses.
This work was supported by National Institutes of Health Grants R37AG025805 and P01AG021600 (to S.L.S.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- bone marrow–derived DC
- dendritic cell
- TLR-activated DC
- Ag-presenting dendritic cell
- *DC activated by TLR agonists and used as APC
- germinal center
- GC B cell
- influenza A virus
- intracellular cytokine staining
- inactivated IAV
- formalin-inactivated PR8
- Poly I:C
- polyinosinic-polycytidylic acid
- A/PR8/34 influenza virus
- pattern recognition receptor
- T follicular helper cell
- CD4 cytotoxic Th cell
- Received June 27, 2016.
- Accepted January 29, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.