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Trudeau Institute, Saranac Lake, NY 12983
Age-related declines in humoral responses contribute to the reduced efficacy of vaccines in older populations. Using an adoptive transfer model, we have shown that age-related intrinsic declines in CD4 T cell function contribute significantly to the reduced humoral responses observed with aging, resulting in reduced B cell expansion and differentiation as well as reduced IgG production. In this current study, we show that the helper function of aged CD4 T cells can be enhanced using a TLR-binding adjuvant or an adjuvant containing proinflammatory (PI) cytokines. The helper function of aged CD4 T cells was also enhanced when PI cytokines were added during in vitro CD4 effector generation. Enhanced helper activity resulted in improved expansion and differentiation of B cells and affinity maturation of IgG. PI cytokines also induced significant production of effector cytokines, including IL-4, IFN-
, IL-17, and IL-21, by both young and aged CD4 T cells. Importantly, we also show that proinflammatory adjuvants can significantly enhance the humoral response in intact aged animals. We propose that one of the mechanisms involved in the ability of adjuvants to enhance both young and aged T cell responses includes driving multifaceted T cell differentiation and production of multiple cytokines by responding CD4 T cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AG21054, AG02160 and AG028878 and by funding from the Kirby Foundation and Trudeau Institute.
2 A.C.M. and S.M.E. made equal contributions to this manuscript.
3 Current address: Department of Microbiology and Immunology, State University of New York Upstate Medical University, 2204 Weiskotten Hall, 750 East Adams Street, Syracuse, NY 13210.
4 Current address: Department of Biological Sciences, University of Delaware, 341 Wolf Hall, Newark, DE 19716.
5 Address correspondence and reprint requests to Dr. Laura Haynes, Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983. E-mail address: lhaynes{at}trudeauinstitute.org
6 Abbreviations used in this paper: GC, germinal cell; PI, proinflammatory; Tpi, T cell effectors generated with PI cytokines; Tfh, T follicular helper; SHM, somatic hypermutation; NP, 4-hydroxy-3-nitrophenyl acetyl; PCC, pigeon cytochrome c; poly(I:C), polyriboinosinic-polyribocytidylic acid; Tg, transgenic; PNA, peanut agglutinin.
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